Biomolecules & Therapeutics 2017; 25(2): 91-104  https://doi.org/10.4062/biomolther.2016.187
Therapeutic Potential of Medicinal Plants and Their Constituents on Lung Inflammatory Disorders
Hyun Pyo Kim*, Hyun Lim, and Yong Soo Kwon
College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
E-mail: hpkim@kangwon.ac.kr, Tel: +82-33-250-6915, Fax: +82-33-255-7865
Received: August 18, 2016; Revised: September 21, 2016; Accepted: October 4, 2016; Published online: December 16, 2016.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Acute bronchitis and chronic obstructive pulmonary diseases (COPD) are essentially lung inflammatory disorders. Various plant extracts and their constituents showed therapeutic effects on several animal models of lung inflammation. These include coumarins, flavonoids, phenolics, iridoids, monoterpenes, diterpenes and triterpenoids. Some of them exerted inhibitory action mainly by inhibiting the mitogen-activated protein kinase pathway and nuclear transcription factor-κB activation. Especially, many flavonoid derivatives distinctly showed effectiveness on lung inflammation. In this review, the experimental data for plant extracts and their constituents showing therapeutic effectiveness on animal models of lung inflammation are summarized.

Keywords: Medicinal plant, Lung inflammation, COPD, Constituent, Flavonoid
INTRODUCTION

Lung inflammatory disorders comprise airway diseases including acute bronchitis and chronic obstructive pulmonary diseases (COPD) such as chronic bronchitis, chronic asthma and emphysema. Particularly, COPD is the 5th leading cause of death worldwide. They are essentially inflammatory diseases. Several classes of drugs such as antitussives, mucolytics and bronchodilators are clinically used to treat the symptom, resulting in a relatively well-controlled condition. However, chronic diseases (COPD) are hard to control with the currently available drugs, which only relieve the symptoms of bronchitis. They do not affect or reverse the pathological progress of COPD. Thus, many pharmaceutical firms are trying to develop new drugs that target the pathological courses of COPD, eventually leading to a complete cure.

Among the drug candidates, leukotriene antagonists and phosphodiesterase 4 (PDE4) inhibitors show some promising results (Reid and Pham, 2012). However, success of low molecular weight drugs remains low since COPD is a very complex disease in etiology and in disease processes as described below. Up to the present, critical target molecules that mainly affect the disease process of COPD have not been found. In this context, plant extracts having complex and diverse chemicals may be favorable. Several plant-based anti-inflammatory drugs are used frequently, especially for acute as well as chronic bronchitis. Examples are the extracts of Hedera helix (Guo et al., 2006), Echinacea purpurea (Sharma et al., 2006) and Pelargonium sidoides (Agbabiaka et al., 2008; Matthys and Funk, 2008). These contain various classes of constituents that demonstrate complex action mechanisms on the above diseases. From many plants, a variety of constituents have been isolated and tested for their potential in treating these disorders. Despite various findings concerning the inhibitory actions of lung inflammation by herbal products, few available systematic reviews are focused on the therapeutic effects on animal models of lung inflammatory disorders. Therefore, in this review, plants that have therapeutic effectiveness on the animal models of lung inflammation are summarized. Plant constituents possessing therapeutic effects on lung inflammation are also discussed. However, this review is not comprehensive. Only findings of English literature are summarized. Anti-asthmatic effects by the plant products are not included.

COPD: ETIOLOGY AND THERAPEUTICS

The pathological factors affecting COPD are diverse and intricately linked. In the deteriorating progress of COPD, various inflammatory mediators are released from epithelial cells and infiltrated inflammatory cells in the lungs, including neutrophils, macrophages and T lymphocytes. It is important that proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-6 and chemokines including IL-8 activate and attract the circulating cells in the pathological process. Transforming growth factor-β (TGF-β) has been reported to cause airway fibrosis, leading to airway destruction. Several approaches for blocking these cytokines or their receptors have been developed for clinical trial against COPD. Among them, IL-1β and IL-18, key molecules of inflammasome, are suggested as potential targets along with other inflammasome components (Rovina et al., 2009; Zhang, 2011).

Reactive oxygen species (ROS) are also critical for provoking COPD. Tobacco smoke contains high concentrations of oxidants and induces a variety of free radicals including ROS. Oxidative stress by excess generation of ROS amplifies the inflammatory responses and develops the pathological stage of COPD. Therefore, several molecules linked to oxidative stress, such as nuclear erythroid-2-related factor 2 (Nrf2), NADPH oxidase, myeloperoxidase and superoxide dismutase may be considered targets for COPD therapy. Also, an imbalance between proteases and anti-proteases leads to alveolar wall destruction. Especially, matrix metalloproteinase (MMP) and neutrophil elastase are intricately regulated in COPD pathology. Several reports indicate that the activation and/or elevated expression of matrix metalloproteinases such as MMP-2, -9 and -12 are closely related to the development of COPD (Churg et al., 2012). Recently sirtuins were demonstrated to be deeply involved in COPD. The level of sirtuin 1 expression is reduced in the lungs of COPD patients. The activation of sirtuin 1 and 6 has been shown to have protective effects against COPD (Chun, 2015) and sirtuin activators may be proposed as candidates for COPD treatment.

Additionally, eicosanoids and nitric oxide (NO) have been shown to be involved. Leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) levels in the exhaled breath condensate of patients with COPD are higher than in healthy subjects (Muntuschi et al., 2003). LTB4 is a potent neutrophil chemoattractant and its concentration in sputum is also increased in COPD patients (Corhay et al., 2009). To reduce LTB4 levels, antagonists of LTB4 receptors and 5-lipoxygenase inhibitors have been developed for the treatment of COPD. Inducible nitric oxide synthase (iNOS) is widely up-regulated in the airways and peripheral lungs of COPD patients (Hesslinger et al., 2009). NO synthesized by iNOS and its oxidant peroxynitrite cause oxidative stress in the lungs. In the animal model, iNOS inhibition by a selective inhibitor was shown to partially improve pulmonary vessel remodeling and functional destruction by smoke-induced emphysema (Seimetz et al., 2011).

Recent investigations suggested that interrupting signal transduction pathways may alleviate COPD progress. Various kinases participate in regulating the expression of inflammatory genes and transcription factors related to COPD. The p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) are proposed as promising representative targets for the development of selective inhibitors. The activation of p38 MAPK induces inflammatory mediators such as IL-1β, IL-8 and MMP in various inflammatory cells, leading to the exacerbation of COPD symptoms. The inhibition of p38 MAPK showed efficacy in a six month clinical trial in COPD patients with ≤2% blood eosinophils (Marks-Konczalik et al., 2015). PI3K-mediated signaling in macrophages and neutrophils is involved in inflammation and immune responses and the activity is up-regulated in the lungs of COPD. It was found that blocking certain isoforms of PI3K reduced pulmonary neutrophilia in a murine smoke model (Doukas et al., 2009). Several PI3K inhibitors have been developed as candidates for COPD therapy so far. In addition, inhibitors targeting transcription factor, nuclear transcription factor-κB (NF-κB), which is involved in the encoding of many inflammatory genes and relevant kinases such as IκB kinase have been also investigated (Schuliga, 2015). However, because some approaches targeting these signaling pathways may have significant problems induced by selectivity, specificity and side effects linked to other pathways, more detailed studies will be needed to determine the best target in treating COPD.

CURRENTLY DEVELOPING DRUG CANDIDATES FOR COPD

Since COPD is characterized by chronic progression and the complexity of parameters priming the disease, previous therapies for COPD have been limited to the use of drugs such as inhaled bronchodilators and corticosteroids, which only improve the symptoms. This means that further detailed clinical trials for many other targets related to COPD are required for the development of new therapy. Recently, COPD management has been focused on anti-inflammatory therapy because COPD is basically an inflammatory disease.

Roflumilast, a PDE4 inhibitor, showed anti-inflammatory effects by inhibiting neutrophil functions and the activation of CD4+ and CD8+ T cells in COPD patients with chronic bronchitis (Pinner et al., 2012). Clinical trials with new PDE4 inhibitors such as RPL554 and CHF6001, which have lower side effects and better efficacy, are ongoing for the development of more potent agents in COPD therapy (Franciosi et al., 2013; Moretto et al., 2015).

Among inflammatory cytokines and chemokines, TNF-α and IL-8 are primarily under development as targets for COPD treatment. TNF-α plays a role in attracting neutrophils and exists in highly variable concentrations in the blood or lungs of patients with COPD. Etanercept, infliximab and adalimumab, antibodies targeting TNF-α or TNF receptor (TNFR), have been developed to alleviate the symptoms of COPD pathogenesis. However, some studies reported adverse effects of infliximab in patients with COPD (Dentener et al., 2008). Etanercept showed no beneficial effects (Aaron et al., 2013). One of the reasons is assumed to be related to the TNF-α concentration of COPD patients and the stage of COPD pathogenesis. Blocking chemokines such as IL-8/C-X-C motif chemokine ligand 8 (CXCL8) with neutralizing antibody reduced neutrophil chemotactic activity in stable COPD patients (Mahler et al., 2004). However, the redundancy in the chemokine network caused the therapeutic effect to be partial. Clinical application with several antagonists of C-X-C motif chemokine receptor 2 (CXCR2, CXCL8 receptor) such as navarixin (SCH 527123, MK-7123) and AZD-5069 was carried out in CODP patients but showed no effective results (Norman, 2013; Rennard et al., 2015). Danirixin (GSK1325756), an oral CXCR2 antagonist is in phase II development for COPD.

Besides antibodies against TNF-α and IL-8, variable antibodies targeting other cytokines have been developed so far. IL-1β and IL-5 are potential targets for COPD therapy. Anti-bodies against IL-1 (Canakinumab and MEDI8986) and IL-5 (Benralizumab and Mepolizumab) were developed, but their efficacy and side effects have to be determined through additional clinical trials, which are currently ongoing. Treatment with antibody blocking IL-5 receptors such as benralizumab, which have been previously developed for asthma treatment, was also attempted in certain patients with COPD and eosinophilia (Brightling et al., 2014) and a clinical trial to evaluate the efficacy and safety is currently underway in patients with COPD. In particular, active IL-1β is produced by nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome, so the inflammasome implicated in COPD is emerging as a new COPD target (Hosseinian et al., 2015). But it is unclear whether the inflammasome directly participates in COPD pathogenesis. Further detailed investigation to confirm the contribution of inflammasome to COPD pathology will be needed.

A current potential target for COPD treatment is p38 MAPK, which is shown to be related to the control of the expression of multiple inflammatory mediators. Recently, some p38 MAPK inhibitors developed for the treatment of rheumatoid arthritis were challenged in clinical trials for COPD (Watz et al., 2014; Norman, 2015). The development of oral p38 MAPK inhibitors such as acumapimod is ongoing for clinical treatment of COPD. Inhaled p38 MAPK inhibitors, PF-03715455 and RV-568, are in Phase I and Phase II clinical trials, respectively (Norman, 2015). However, the development of PH-797804 and losmapimod was terminated for COPD treatment because they showed no improved effects compared to roflumilast, a PDE4 inhibitor. Another kinase, PI3K, which is upregulated in the lungs of COPD patients, can also be a potential target for CODP therapy (To et al., 2010). Although TG100-115, PI3Kγ and -δ inhibitor, was proven to be effective in the mouse smoke-induced lung inflammation model (Doukas et al., 2009), the clinical development has been discontinued at present. Recent study suggested that targeting PI3Kδ was beneficial for the treatment of respiratory diseases (Sriskantharajah et al., 2013). GSK2269557, an inhaled PI3Kδ inhibitor, is currently undergoing clinical trial for COPD.

MMP-9, MMP-12 and neutrophil elastase play important roles in the breakdown of collagen and elastin fibers in emphysema patients. Several protease inhibitors targeting these proteases have been developed but discontinued for various reasons such as efficacy problems and side effects in clinical trials. To date, various drug candidates that block the signaling pathway related to the induction mechanisms of COPD pathogenesis have been developed. They showed effectiveness in several animal models. But most human trials have been stopped due to their low efficacy and major side effects. Thus, continual efforts to define new target molecules and to find agents that interrupt various signaling processes are needed. As an alternative to these efforts, plants and plant products have been studied with the hope of finding new and effective agents to treat these inflammatory lung disorders.

ANIMAL MODELS OF LUNG INFLAMMATION

There are several animal models of lung inflammation used for establishing the therapeutic effects of target compounds. For acute lung inflammation, the most widely used model is the lipopolysaccharide (LPS)-induced acute lung injury (inflammation) model (Rojas et al., 2005; Matute-Bello et al., 2008). Mice used are ICR, BALB/c, C57BL/6, etc. LPS is either administered via the intratracheal or intranasal route. Sometimes, rats are used and LPS is intratracheally administered in this case. Rarely, sulfur dioxide (SO2) gas and chlorine gas are used as inflammagens instead of LPS. From the bronchoalveolar lavage fluid (BALF), the cells are counted. Infiltrated neutrophils and macrophages are major cells. The lung tissues show typical inflammatory conditions such as alveolar wall hyperplasia and many infiltrated inflammatory cells can be observed in histological samples. In LPS-induced acute lung injury (ALI) model, proinflammatory cytokines/chemokines as well as oxidative stress contribute to provoking inflammatory responses. Thus, anti-oxidative treatments such as Nrf2 pathway activation attenuate lung inflammatory responses (Kim et al., 2010). Proinflammatory cytokines/chemokines are frequently detected in the BALF. Generally, TNF-α, IL-6 and IL-8 are elevated. In our study, IL-6 and IL-8 levels are increased in the BALF 16 h after LPS treatment by the nasal route in ICR mice (Lim et al., 2013). In these animal models, the NF-κB activation pathway plays an essential role in provoking lung inflammation. The MAPK pathway is also involved.

In animal models of chronic lung inflammation, cigarette smoke-induced lung inflammation may be used. Cigarette smoke exposure to mice and rats for several days or weeks produces COPD-similar changes in the affected lung tissues (Wright et al., 2008). Inflammatory cells are recruited to lung tissues. Elevated numbers of goblet cells producing mucins are also observed in some cases using Periodic acid-Schiff (PAS) staining. Similar changes are also obtained in an animal model of LPS/elastase-treated mice (Ganesan et al., 2010; Lee et al., 2012). Elastase administered to the lung for weeks sometimes destroys the alveolar layer to produce large emphysema-like lesions. However, this change may be confined to several strains of mice. In our experiment with ICR mice, this change was hardly observed, although elevated levels of infiltrated inflammatory cells in the BALF could be detected (data not shown). The similar finding was also demonstrated that cigarette smoke-induced lung inflammatory responses were varied on mice strains (Morris et al., 2008). To date, animal models mimicking human COPD have not been adequately established. The relevance of animal models and human COPD is not satisfactory. Generally, agents showing activity in animal models of chronic lung inflammation do not show high effectiveness in clinical trials. Thus, new animal models need to be established for successful development of new drugs against COPD.

THE INHIBITION OF PLANT EXTRACTS AGAINST IN VIVO ANIMAL MODELS OF LUNG INFLAMMATION

In this review, findings using the septic shock model are not mentioned since intraperitoneal or intravenous injection of endotoxin (LPS) provokes systemic inflammation leading to the cytokine storm instead of local airway inflammation in the lung. LPS-induced acute lung injury (ALI) produces local lung inflammation. Some potential effects of herbal products on ALI were summarized previously (Favarin et al., 2013). Recently, effects of dozens of plant-derived compounds on lung inflammatory diseases including asthma and COPD models are also described (Santana et al., 2016).

Many medicinal plants have shown regulatory effects on lung inflammation at doses of approximately 100–300 mg/kg as summarized in Table 1. On the other hand, Gleditsia sinensis, Glycyrrhiza uralensis, Lonicera japonica, Taraxacum officinale extracts and the petroleum ether fraction of Viola yedoensis showed potent inhibitory activity by oral administration against LPS-induced lung inflammation at low doses (Xie et al., 2009; Liu et al., 2010; Choi et al., 2012; Li et al., 2012b; Kao et al., 2015). They showed significant inhibition at doses as low as 3 mg/kg. Gleditsia sinensis is known to possess anti-allergic and anti-inflammatory activity (Dai et al., 2002; Ha et al., 2008). It contains various triterpenoids as major components (Lim et al., 2005). Many triterpenoids were previously found to possess anti-inflammatory activity (Kim et al., 1999). All this information suggests that G. sinensis has potential for treating lung inflammatory diseases.

Lonicera japonica is a well-known anti-inflammatory agent (Lee et al., 1998). The entire plant including the leaves and flowers is widely used in traditional medicine as an anti-inflammatory agent especially for treating upper airway inflammatory diseases. L. japonica is an ingredient of many complex prescriptions for lung inflammatory disease in ancient literatures. It contains iridoids and flavonoids as major components, which show significant anti-inflammatory activity (Lee et al., 1995).

In addition, the alkaloid fractions of Aconitum tanguticum and Alstonia scholaris inhibited LPS-induced ALI in rats at low doses (Wu et al., 2014a; Zhao et al., 2016).

Ginkgo biloba leaves extract showed considerable inhibition of lung inflammation in LPS-induced ALI at low doses when they were administered intraperitoneally (Huang et al., 2013). G. biloba leaves extract has been used to enhance blood circulation, prevent neurodegeneration and enhance cognitive function. The anti-inflammatory action of G. biloba leaves is well known (Ilieva et al., 2004). G. biloba leaves also exert an anti-asthmatic effect (Babayigit et al., 2009). Thus, this medicinal plant material has the potential to treat lung-related inflammatory/allergic diseases. The major constituents are ginkgolides and flavonoids. Many flavonoid derivatives show inhibitory action on lung inflammation as described below.

Against the COPD model induced by cigarette smoke, several plant extracts such as Azadirachta indica, Callicarpa japonica, Cnidium monnieri, Euterpe oleracea, Galla chinensis, Juglans regia, Schisandra chinensis and Stemona tuberosa were found to inhibit inflammatory responses in the lung (Qamar and Sultana, 2011; Koul et al., 2012; Moura et al., 2012; Kwak and Lim, 2014; Lee et al., 2014, 2015a, 2015d; Zhong et al., 2015), suggesting their therapeutic potential in chronic lung inflammatory diseases. Particularly, S. chinensis has been widely used for lung disorders in traditional medicine in the East Asia region, and the findings above provide the scientific basis for this traditional use. This extract was found to inhibit acute as well as chronic inflammatory condition of lung inflammation. But no report is available establishing the activity of its constituents. The therapeutic potential of the major constituents such as schizandrin and gomisins remains to be discovered in the near future.

Hedera helix (ivy leaf, Guo et al., 2006), Echinacea purpurea (Sharma et al., 2006; Agbabiaka et al., 2008) and Pelargonium sidoides (Matthys and Funk, 2008) are frequently used for treating bronchitis in Asian and European countries. The extracts alleviate the symptoms of acute and chronic bronchitis such as sputum production and coughing. Ivy leaves extract has been prescribed for treating bronchitis under the name Prospan® (Ahngook Pharm., Seoul, Korea). Pelagonium sidoides ethanol extract under the name Umckamin syrup® (Han Wha Pharma Co., Seoul, Korea) is used for acute bronchitis. It is significant to note that ivy extract also showed some effectiveness against influenza A virus infection in mice when simultaneously administered with the antiviral drug, Tamiflu (Hong et al., 2015a). The therapeutic effectiveness of some herbal remedies in COPD patients has been summarized (Guo et al., 2006). In human clinical study, some ginseng products showed promising results in COPD patients (Gross et al., 2002). Recently, we have found that some ginseng products and ginsenosides clearly inhibited lung inflammatory responses in a mouse model of ALI (data not shown).

Sometimes, a combination of herbal plants gives more promising results. Several herbal mixtures were also demonstrated to possess inhibitory action on lung inflammation. Particularly, Xia-Bai-San demonstrated efficacy at the dose of 1 mg/kg against LPS-induced ALI (Yeh et al., 2006). Recently, a new formula, Synatura® (Ahngook Pharm., Seoul, Korea) containing ivy leaf and Coptis chinensis was developed for treating chronic bronchitis.

THE INHIBITION OF PLANT CONSTITUENTS AGAINST IN VIVO ANIMAL MODELS OF LUNG INFLAMMATION AND ACTION MECHANISMS

Resveratrol (stilbenoid, 48) (Fig. 1) was found to show strong inhibitory action against acute lung inflammation and the COPD model (Donnelly et al., 2004; Liu et al., 2014a). Resveratrol showed effectiveness through the reduction of proinflammatory cytokine and prostanoid generation. In one study, resveratrol was revealed to reduce the inflammatory responses in cigarette smoke-induced COPD mice by inhibiting NF-κB activation and the elevation of heme oxygenase-1 (HO-1) expression (Liu et al., 2014a). The detailed anti-inflammatory action mechanisms of resveratrol, curcumin and glycyrrhetic acid are well summarized in the previous review paper (Sharafkhaneh et al., 2007).

Some phenolics also showed effectiveness against lung inflammation by oral administration. These include apocynin (8), caffeic acid derivative (13), ellagic acid (19), paeonol (39) and zingerone (59) (Table 2). Particularly, paeonol, a major ingredient from Paeonia suffruticosa, inhibited a mice model of COPD, cigarette smoke-induced lung inflammation at 10 mg/kg/day (Liu et al., 2014b). This finding is well correlated with the inhibitory potential of P. suffruticosa extract against LPS-induced ALI in rats (Fu et al., 2012). Ellagic acid protected against lung damage induced by acid treatment (Cornélio Favarin et al., 2013). This compound was demonstrated to reduce IL-6 production along with the increase of anti-inflammatory cytokine, IL-10, in BALF, but, no inhibition of NF-κB and activator protein-1 (AP-1) activation was observed. Similar pharmacological mechanisms were also found in zingerone (phenol) treatment for LPS-induced ALI (Xie et al., 2014).

The benzoic acid derivative, protocatechuic acid (46), significantly inhibited LPS-induced ALI by inhibiting NF-κB activation via inhibiting IκBα degradation and the translocation of p65 to the nucleus (Wei et al., 2012). Limonene (monoterpene, 30) also inhibited LPS-induced ALI by the downregulation of MAPK and NF-κB activation (Chi et al., 2013). Linalool (31) demonstrated inhibitory activity in the cigarette smoke-induced COPD model by the same action mechanism of blocking NF-κB activation (Ma et al., 2015b). Phillyrin (lignan, 41) reduced proinflammatory cytokine production mainly by inhibiting MAPK and NF-κB activation in LPS-induced ALI (Zhong et al., 2013b). The same action mechanisms were also demonstrated by schisantherin A (53) treatment inhibiting MAPK and NF-κB activation (Zhou et al., 2014). It is important to mention that berberine (12) intraperitoneally injected reduced the inflammatory response of cigarette smoke-induced COPD model in mice. The compound inhibited the activation of extracellular signal-regulated kinase (ERK) and p38 MAPK activation in lung tissue (Xu et al., 2015). Shikonin (52) and stevioside (54) reduced the inflammatory response of LPS-induced ALI by inhibiting NF-κB activation (Bai et al., 2013; Yingkun et al., 2013). Asperuloside (iridoid, 9) inhibited LPS-induced ALI mainly via the inhibiting MAPK and NF-κB activation (Qiu et al., 2016). Prime-O-glucosylcimifugin (chromone, 45) also inhibited lung inflammation by a similar mechanism of MAPK and NF-κB inhibition (Chen et al., 2013). Although many compounds have been found to attenuate lung inflammation by interrupting the MAPK and NF-κB pathways, it is interesting that cannabidiol (14) inhibited LPS-induced ALI at least partly by stimulating the adenosine A(2A) receptor (Ribeiro et al., 2012). Part of the attenuating effect of eriodictyol (21) against LPS-induced ALI was due to the activation of the Nrf2 pathway (Zhu et al., 2015).

Most of all, various flavonoids have been shown to inhibit lung inflammation. Flavonoids are well-known anti-inflammatory plant constituents. Certain flavonoids have shown inhibitory action in various animal models of inflammation. For example, some flavonoids were revealed to inhibit the animal models of acute inflammation: paw edema, ear edema and pleurisy. They also inhibited animal models of chronic inflammation: adjuvant-induced arthritis and collagen-induced arthritis. Certain derivatives inhibited lung inflammation. Flavone derivatives including flavone (24), tricetin (26), luteolin (32), apigenin-7-glucoside (7), baicalein (10) and baicalin (11), flavonol derivatives such as afzelin (2), hyperoside (3), quercitrin (4), morin (37), quercetin (47) and fisetin (25), isoflavones such as tectorigenin (56), flavanones such as eriodictyol (21), naringin (38), hesperidin (28) and sakuranetin (49) were demonstrated to possess inhibitory activity in lung inflammation models. Quercetin, baicalin and naringin orally administered were effective in the COPD model (Ganesan et al., 2010; Li et al., 2012a; Nie et al., 2012). Particularly, quercetin inhibited lung inflammation and mucus production in the cigarette smoke-induced COPD model (Yang et al., 2012). This inhibitory action might be mediated by inhibiting oxidative stress, inhibiting NF-κB activation and epidermal growth factor receptor (EGFR) phosphorylation. The structurally related flavonoid, baicalein, inhibited LPS-induced ALI in rats by augmenting Nrf2/HO-1 pathways and inhibiting NF-κB activation (Tsai et al., 2014). Luteolin reduced lung inflammation possibly by inhibiting NF-κB activation via the inhibition of MAPK and AKT/Protein kinase B (Lee et al., 2010). Fisetin treatment by oral administration reduced proinflammatory molecule production such as IL-1β, IL-6, TNF-α, macrophage inflammatory protein-1α (MIP-1α), MIP-2 and IκBα (Geraets et al., 2009). Similar inhibitory mechanisms were revealed in tectorigenin which reduced lung inflammation via inhibiting the p65 NF-κB component (Ma et al., 2014). Hesperidin reduced the production of proinflammatory cytokines including TNF-α and IL-6, whereas it increased the production of anti-inflammatory cytokines such as IL-4 and IL-10. These actions of hesperidin might be mediated by the interruption of NF-κB and AP-1 pathways (Yeh et al., 2007a). Thus it is concluded that certain flavonoids act as inhibitory agents against lung inflammatory diseases. Their action mechanisms include anti-oxidative action and NF-κB inhibition. Indeed, herbal extracts that have flavonoids as major constituents have been used against lung inflammation. For example, Morus alba, which contains prenylated flavonoids as major constituents, has been used in traditional medicine to treat lung inflammatory disorders (Nomura, 2001). Scutellaria baicalensis has also been used in lung inflammatory conditions. This plant material contains various types of flavone derivatives such as baicalein and baicalin. Baicalein and especially baicalin exert strong inhibitory action against acute as well as chronic lung inflammation by oral administration (Huang et al., 2008; Li et al., 2012a).

In the elastase-induced emphysema model, NF-κB was also activated in the lung tissue. Under this condition, sakuranetin reduced the NF-κB response (Taguchi et al., 2015). It also regulated the expression of MMPs. In the elastase/LPS-induced COPD model, quercetin reduced inflammatory responses with concomitant inhibition of MMP-9 and −12 (Ganesan et al., 2010).

Other groups of plant constituents also demonstrated inhibitory action on lung inflammation. Some diterpenoids and triterpenoids have demonstrated inhibitory activity against lung inflammation. For instance, the triterpenoid saponins are major constituents of Hedera helix, which is used for lung inflammation (Gepdiremen et al., 2005; Hocaoglu et al., 2012). Platycodin D (44), a triterpenoid saponin from Platycodon grandiflorum, also showed inhibitory action against ALI (Tao et al., 2015). This compound was found to inhibit the expression of NF-κB, caspase-3 and Bax. P. grandiflorum has been used as an expectorant (State Pharmacopoeia Commission of PR China, 2000). Methyl protodioscin (34), a steroidal saponin, showed inhibitory action agaisnt LPS-induced ALI at 30–60 mg/kg (Lee et al., 2015c). Taraxasterol (55) from Taraxacum officinale, in this case through intraperitoneal injection, showed inhibitory action against lung inflammation (San et al., 2014). This inhibitory action was mediated by the inhibition of MAPK and NF-κB pathways. Another triterpene derivative, mogroside V (35), reduced lung inflammation by the downregulation of COX-2 and iNOS via inhibiting NF-κB activation (Shi et al., 2014). The famous diterpenoid, triptolide (57) from Trypterygium wilfordii, was also shown to inhibit LPS-induced lung inflammation at concentrations as low as 1 mg/kg via intraperitoneal injection (Wei and Huang, 2014). Especially, triptolide inhibited the activation of MAPK and NF-κB pathways, and toll-like receptor 4 (TLR4) expression in LPS-induced ALI in mice. Esculentoside A (saponin, 22) also reduced TNF-α and IL-6 production possibly via inhibition of MAPK and NF-κB pathways (Zhong et al., 2013a).

Some coumarin derivatives also possess inhibitory action against lung inflammation. Examples are columbianadin (17), esculin (23) and imperatorin (29) (Sun et al., 2012; Lim et al., 2014; Tianzhu and Shumin, 2015). Esculin inhibited LPS-induced ALI by inhibiting the activation of myeloid differentiation primary response gene 88 (MyD88) (an upstream molecule of NF-κB) and NF-κB p65 activation (Tianzhu and Shumin, 2015).

Recently, moracin M (arylbenzofuran, 36) was found to inhibit LPS-induced ALI at 20–60 mg/kg (Lee et al., 2016). Moracin M was found to suppress NF-κB activation in the inflamed lung. This compound is a minor constituent in Morus alba, which showed significant inhibition against the same animal model (Lim et al., 2013). These results may support the scientific basis of M. alba for treating lung diseases.

As described above, reports on many plant constituents demonstrating inhibitory action on lung inflammation are increasing continuously, and some have demonstrated promising results. In the near future, the clinical effectiveness of some molecules may be proven in human trials.

CONCLUSION AND FUTURE PROSPECTS

Various plant extracts possess potential therapeutic effectiveness against lung inflammatory disorders including COPD. Additionally, many different classes of plant constituents were found to inhibit inflammatory responses in the lung. Especially, flavonoids are promising therapeutics since they affect signaling pathways essential to lung inflammation.

Up to the present, the regulatory effects of many natural products on NF-κB activation have been widely demonstrated. Despite the importance of NF-κB in lung inflammatory disorders, there are some contradicting results showing that NF-κB does not exert a role in cigarette smoke-induced COPD models of mice and in human lungs (Rastrick et al., 2013). Other cellular pathways need to be evaluated to examine the effectiveness of natural products. For instance, sirtuins were recently described as target molecules in COPD disorders. MMPs are also important for controlling lung elasticity. With continuous study, some plant extracts and constituents will hopefully be developed as new disease modifying drugs acting on lung inflammatory disorders.

ACKNOWLEDGMENTS

The authors declare no conflict of interest. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2016R1A2B4007756), 2016 Research Grant from Kangwon National University (No. 520160100) and BK21 PLUS program from the Ministry of Education, Republic of Korea.

Figures
Fig. 1. The chemical structures of some selected plant constituents mentioned in this study.
Tables

Inhibition of the animal models of lung inflammation by various plant extracts

PlantsExtractsDoses (mg/kg)a)Inflammagen usedb)Ref.
Acanthopanax senticosusc)20 (i.v.)LPS (i.t.)Fei et al. (2014)
Aconitum tanguticumAlkaloid fraction30–60LPS (rat)Wu et al. (2014a)
Alisma orientale Juzepzuk80% ethanol300–1,200LPSHan et al. (2013)
Angelica decursiva70% ethanol400LPSLim et al. (2014)
Antrodia camphorataMethanol25–100LPSHuang et al. (2014a)
Alstonia scholarisAlkaloid fraction7–30LPS (i.t.) (rat)Zhao et al. (2016)
Azadirachta indicaWater100/dayCigarette smokeKoul et al. (2012)
Callicarpa japonica Thunb.Methanol15–30/dayCigarette smokeLee et al. (2015d)
Canarium lyi C.D. Dai & YakovlevMethanol30/dayLPSHong et al. (2015b)
Chrysanthemum indicumSupercritical CO2 extract40–120/dayLPS (i.t.)Wu et al. (2014b)
Cnidium monnieriWater50–200/dayCigarette smoke extract/LPS (i.t.)Kwak and Lim (2014)
Eleusine indica400 (i.p.)LPSDe Melo et al. (2005)
Euterpe oleracea Mart.50% ethanol300/dayCigarette smokeMoura et al. (2012)
Galla chinensis100/dayCigarette smokeLee et al. (2015a)
Ginkgo bilobaEgb7610.01–1 (i.p.)LPS (i.t.)Huang et al. (2013)
Gleditsia sinensisWater3.3–10/dayLPSChoi et al. (2012)
Glycyrrhiza uralensisFlavonoid fraction3–30LPS (i.t.)Xie et al. (2009)
Houttuynia cordata70% ethanol400LPSLee et al. (2015b)
Juglans regia L. kernelMethanol50–100/dayCigarette smoke (rat)Qamar and Sultana (2011)
Lonicera japonica flos50% ethanol0.4–40LPS (i.t.)Kao et al. (2015)
Lysimachia clethroides DubyMethanol20–100 (i.p.)LPSShim et al. (2013)
Mikania glomerata Spreng and Mikania laevigata Schultz Bip. Ex Baker70% ethanol100 (s.c.)Mineral coal dust (i.t.) (rat)Freitas et al. (2008)
Morus alba70% ethanol200–400LPSLim et al. (2013)
Nigella sativaHydroethanolic extract80/daySulfur mustard (guinea-pigs)Hossein et al. (2008)
Paeonia suffruticosaGranule2,000LPS (i.t) (rat)Fu et al. (2012)
Phellodendri cortexMethanol100–400LPS (i.t.)Mao et al. (2010)
Punica granatum0.9% NaCl200 (i.p.)LPS (i.t.)Bachoual et al. (2011)
Rabdosia japonica var. glaucocalyxFlavonoid fraction6.4–25.6/dayLPS (i.t.)Chu et al. (2014)
Schisandra chinensis BaillonWater10–100LPSBae et al. (2012)
Schisandra chinensis BaillonAqueous ethanol1,000/dayCigarette smoke-induced cough hypersensitivity (guinea pig)Zhong et al. (2015)
Stemona tuberosaWater50–200/dayCigarette smokeLee et al. (2014)
Taraxacum officinaleWater2.5–10/dayLPSLiu et al. (2010)
Taraxacum mongolicum hand.-MazzWater5,000–10,000LPSMa et al. (2015a)
Uncaria tomentosaWaterOzoneCisneros et al. (2005)
Viola yedoensisPetroleum ether2–8LPSLi et al. (2012b)
Formula: Dangkwisoo-sanMixture100–1,000/dayLPSLyu et al. (2012)
Formula: Gingyo-sanMixture1–2LPS (i.t.)Yeh et al. (2007b)
Formula: Hochu-ekki-to (TJ-41)Mixture1,000/dayLPSTajima et al. (2006)
Formula: Xia-Bai-SanMixture1LPS (i.t.)Yeh et al. (2006)
Formula: BP+LJMixture100–400LPS (i.t.) (rat)Ko et al. (2011)

All extracts were orally administered unless otherwise stated.

Mice were used as experimental animals unless otherwise indicated. Administration route of inflammagens was intranasal. Intratracheal route (i.t.) was indicated. Cigarette smoke was administered by inhalation route.

Due to the insufficient information provided, space remained blank.

Inhibition of the animal models of lung inflammation by plant constituents

ConstituentClassPlant originDoses (mg/kg)a)Inflammagen usedb)Reference
Acteoside (1)PhenylethanoidRehmannia glutinosa30–60 (i.p.)LPS (i.t.)Jing et al. (2015)
Afzelin (2), hyperoside (3), quercitrin (4)FlavonoidHouttuynia cordata100, 100, 100LPSLee et al. (2015b)
Alpinetin (5)FlavonoidAlpinia katsumadai50 (i.p.)LPS (i.t.)Huo et al. (2012)
Andrographolide (6)DiterpeneAndrographis paniculata1/day (i.p.)Cigarette smokeYang et al. (2013)
Apigenin-7-glucoside (7)Flavonoidc)2.5–10 (i.p.)LPS (i.t.)Li et al. (2015)
Apocynin (8)PhenolPicrorhiza kurroa0.002–0.2/mlLPS (hamster)Stolk et al. (1994)
Asperuloside (9)Iridoid20–80 (i.p.)LPSQiu et al. (2016)
Baicalein (10)FlavonoidScutellaria baicalensis20 (i.p.)LPS (i.t.) (rat)Tsai et al. (2014)
Baicalin (11)FlavonoidScutellaria baicalensis25–100/dayCigarette smokeLi et al. (2012a)
Baicalin (11)FlavonoidScutellaria baicalensis20LPS (i.t.) (rat)Huang et al. (2008)
Berberine (12)Alkaloid5–10/day (i.p.)Cigarette smokeXu et al. (2015)
Caffeic acid phenethyl ester (13)PhenolHoney-bee propolis10 μmol/kg/dayCigarette smoke (rabbit)Sezer et al. (2007)
Cannabidiol (14)CannabinoidCannabis sativa20LPSRibeiro et al. (2012)
Carvacrol (15)MonoterpenePlectranthus amboinicus20–80 (i.p.)LPSFeng and Jia (2014)
Cepharanthine (16)AlkaloidStephania cepharantha Hayata5 (i.p.)LPSHuang et al. (2014b)
Columbianadin (17)CoumarinAngelica decursiva20–60LPSLim et al. (2014)
p-cymene (18)Monoterpene25–100 (i.p.)LPS (i.t.)Xie et al. (2012)
Ellagic Acid (19)Phenol10AcidCornélio Favarin et al. (2013)
Ergosterol (20)SterolScleroderma polyrhizum Pers.25–50LPSZhang et al. (2015)
Eriodictyol (21)FlavonoidDracocephalum rupestre30/dayLPSZhu et al. (2015)
Esculentoside A (22)SaponinPhytolacca esculenta15–60LPSZhong et al. (2013a)
Esculin (23)Coumarin20–40LPS (i.t.)Tianzhu and Shumin (2015)
Flavone (24), fisetin (25), tricetin (26)Flavonoid22.2, 28.6, 30.2LPS (i.t.)Geraets et al. (2009)
Gossypol (27)Sesquiterpene15 (i.p.)LPSHuo et al. (2013b)
Hesperidin (28)Flavonoid200LPS (i.t.)Yeh et al. (2007a)
Imperatorin (29)Coumarin15–30LPSSun et al. (2012)
Limonene (30)Monoterpene25–75 (i.p.)LPS (i.t.)Chi et al. (2013)
Linalool (31)MonoterpeneAromatic plant25 (i.p.)LPSHuo et al. (2013a)
Linalool (31)MonoterpeneAromatic plant10–40 (i.p).Cigarette smokeMa et al. (2015b)
Luteolin (32)FlavonoidLonicera japonica70 μmol/kg (i.p.)LPS (i.t.)Lee et al. (2010)
Mangiferin (33)XanthoneMangifera indica L.450–4,050/dayLPSWang et al. (2015)
Methyl protodioscin (34)Steroidal saponinAsparagus cochinchinensis30–60LPSLee et al. (2015c)
Mogroside V (35)Triterpene saponinMomordica grosvenori2.5–10LPSShi et al. (2014)
Moracin M (36)2-arylbenzofuranMorus alba20–60LPSLee et al. (2016)
Morin (37)Flavonoid20–40LPSTianzhu et al. (2014)
Naringin (38)Flavonoid20–80/dayCigarette smoke (rat)Nie et al. (2012)
Paeonol (39)PhenolPaeonia suffruticosa10/dayCigarette smokeLiu et al. (2014b)
Patchouli alcohol (40)SesquiterpenePogostemon cablin10–40 (i.p.)LPSYu et al. (2015)
Phillyrin (41)LignanForsythia suspensa10–20LPSZhong et al. (2013b)
Picroside Ii (42)IridoidPicrorhiza scrophulariiflora0.5–1 (i.t.)LPS (i.t.)Noh et al. (2015)
Pinocembrin (43)FlavonoidAlpinia katsumadai20–50 (i.p.)LPSSoromou et al. (2012)
Platycodin D (44)Triterpenoid saponinPlatycodon grandiflorum50–100LPS (i.t.)Tao et al. (2015)
Prime-O-glucosylcimifugin (45)ChromoneSaposhnikovia divaricata2.5–10 (i.p.)LPSChen et al. (2013)
Protocatechuic acid (46)Benzoic acid30 (i.p.)LPSWei et al. (2012)
Quercetin (47)Flavonoid10/dayLPS/elastaseGanesan et al. (2010)
Quercetin (47)Flavonoid25–30/day (i.p.)Cigarette smoke (rat)Yang et al. (2012)
Resveratrol (48)StilbeneLPSDonnelly et al. (2004)
Resveratrol (48)Stilbene1–3/dayCigarette smoke (3 days)Liu et al. (2014a)
Sakuranetin (49)FlavonoidBaccharis retusa20 (i.n.)Elastase-induced emphysemaTaguchi et al. (2015)
Schaftoside (50), vitexin (51)FlavonoidEleusine indica0.4, 0.4 (i.p.)LPSDe Melo et al. (2005)
Shikonin (52)NaphthoquinoneLithospermum erythrorhizon12.5–50LPS (i.t.)Bai et al. (2013)
Schisantherin A (53)LignanSchisandra sphenanthera10–40LPSZhou et al. (2014)
Stevioside (54)DiterpeneStevia rebaudiana12.5–50LPSYingkun et al. (2013)
Taraxasterol (55)TriterpeneTaraxacum officinale2.5–10 (i.p.)LPSSan et al. (2014)
Tectorigenin (56)FlavonoidBelamcanda chinensis5–10 (i.v.)LPS (i.t.)Ma et al. (2014)
Triptolide (57)DiterpeneTripterygium wilfordii0.005–0.015LPSWei and Huang (2014)
Usnic acid (58)DibenzofuranLichen species25–100/dayLPSSu et al. (2014)
Zingerone (59)Phenol10–40LPSXie et al. (2014)

All compounds were orally administered unless otherwise stated.

Mice were used as experimental animals unless otherwise indicated. Administration route of inflammagens was intranasal. Intratracheal route (i.t.) was indicated. Cigarette smoke was administered by inhalation route.

Constituents from commercial sources were purchased or could be isolated from various plant sources.

References
  1. Aaron, SD, Vandemheen, KL, Maltais, F, Field, SK, Sin, DD, Bourbeau, J, Marciniuk, DD, FitzGerald, JM, Nair, P, and Mallick, R (2013). TNFα antagonists for acute exacerbations of COPD: a randomised double-blind controlled trial. Thorax. 68, 142-148.
    CrossRef
  2. Agbabiaka, TB, Guo, R, and Ernst, E (2008). Pelargonium sidoides for acute bronchitis: a systematic review and meta-analysis. Phytomedicine. 15, 378-385.
    Pubmed CrossRef
  3. Babayigit, A, Olmez, D, Karaman, O, Ozogul, C, Yilmaz, O, Kivcak, B, Erbil, G, and Uzuner, N (2009). Effects of Ginkgo biloba on airway histology in a mouse model of chronic asthma. Allergy Asthma Proc. 30, 186-191.
    Pubmed CrossRef
  4. Bachoual, R, Talmoudi, W, Boussetta, T, Braut, F, and El-Benna, J (2011). An aqueous pomegranate peel extract inhibits neutrophil myeloperoxidase in vitro and attenuates lung inflammation in mice. Food Chem Toxicol. 49, 1224-1228.
    Pubmed CrossRef
  5. Bae, H, Kim, R, Kim, Y, Lee, E, Kim, HJ, Jang, YP, Jung, S-K, and Kim, J (2012). Effects of Schisandra chinensis Baillon (Schizandraceae) on lipopolysaccharide induced lung inflammation in mice. J Ethnopharmacol. 142, 41-47.
    Pubmed CrossRef
  6. Bai, GZ, Yu, HT, Ni, YF, Li, XF, Zhang, ZP, Su, K, Lei, J, Liu, BY, Ke, CK, Zhong, DX, Wang, YJ, and Zhao, JB (2013). Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice. J Surg Res. 182, 303-311.
    CrossRef
  7. Brightling, CE, Bleecker, ER, Panettieri, RA, Bafadhel, M, She, D, Ward, CK, Xu, X, Birrell, C, and van der Merwe, R (2014). Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2, 891-901.
    Pubmed KoreaMed CrossRef
  8. Chen, N, Wu, Q, Chi, G, Soromou, LW, Hou, J, Deng, Y, and Feng, H (2013). Prime-O-glucosylcimifugin attenuates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol. 16, 139-147.
    Pubmed CrossRef
  9. Chi, G, Wei, M, Xie, X, Soromou, LW, Liu, F, and Zhao, S (2013). Suppression of MAPK and NF-κB pathways by limonene contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation. 36, 501-511.
    CrossRef
  10. Choi, JY, Kwun, MJ, Kim, KH, Lyu, JH, Han, CW, Jeong, HS, Ha, KT, Jung, HJ, Lee, BJ, Sadikot, RT, Christman, JW, Jung, SK, and Joo, M (2012). Protective effect of the fruit hull of Gleditsia sinensis on LPS-induced acute lung injury is associated with Nrf2 activation. Evid Based Complement Alternat Med. 2012, 974713.
    Pubmed KoreaMed CrossRef
  11. Chu, CJ, Xu, NY, Li, XL, Xia, L, Zhang, J, Liang, ZT, Zhao, ZZ, and Chen, DF (2014). Rabdosia japonica var. glaucocalyx flavonoids fraction attenuates lipopolysaccharide-induced acute lung injury in mice. Evid Based Complement Alternat Med. 2014, 894515.
    Pubmed KoreaMed CrossRef
  12. Chun, P (2015). Role of sirtuins in chronic obstructive pulmonary disease. Arch Pharm Res. 38, 1-10.
    CrossRef
  13. Churg, A, Zhou, S, and Wright, JL (2012). Series “matrix metalloproteinases in lung health and disease”: Matrix metalloproteinases in COPD. Eur Respir J. 39, 197-209.
    CrossRef
  14. Cisneros, FJ, Jayo, M, and Niedziela, L (2005). An Uncaria tomentosa (cat’s claw) extract protects mice against ozone-induced lung inflammation. J Ethnopharmacol. 96, 355-364.
    CrossRef
  15. Corhay, JL, Henket, M, Nguyen, D, Duysinx, B, Sele, J, and Louis, R (2009). Leukotriene B4 contributes to exhaled breath condensate and sputum neutrophil chemotaxis in COPD. Chest. 136, 1047-1054.
    Pubmed CrossRef
  16. Cornélio Favarin, D, Martins Teixeira, M, Lemos de Andrade, E, de Freitas Alves, C, Lazo Chica, JE, Arterio Sorgi, C, Faccioli, LH, and Paula Rogerio, A (2013). Anti-inflammatory effects of ellagic acid on acute lung injury induced by acid in mice. Mediators Inflamm. 2013, 164202.
    Pubmed KoreaMed CrossRef
  17. Dai, Y, Chan, YP, Chu, LM, and Bu, PP (2002). Antiallergic and anti-inflammatory properties of the ethanolic extract from Gleditsia sinensis. Biol Pharm Bull. 25, 1179-1182.
    Pubmed CrossRef
  18. De Melo, GO, Muzitano, MF, Legora-Machado, A, Almeida, TA, De Oliveira, DB, Kaiser, CR, Koatz, VL, and Costa, SS (2005). C-glycosylflavones from the aerial parts of Eleusine indica inhibit LPS-induced mouse lung inflammation. Planta Med. 71, 362-363.
    Pubmed CrossRef
  19. Dentener, MA, Creutzberg, EC, Pennings, HJ, Rijkers, GT, Mercken, E, and Wouters, EF (2008). Effect of infliximab on local and systemic inflammation in chronic obstructive pulmonary disease: a pilot study. Respiration. 76, 275-282.
    Pubmed CrossRef
  20. Donnelly, LE, Newton, R, Kennedy, GE, Fenwick, PS, Leung, RH, Ito, K, Russell, RE, and Barnes, PJ (2004). Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol. 287, L774-L783.
    Pubmed CrossRef
  21. Doukas, J, Eide, L, Stebbins, K, Racanelli-Layton, A, Dellamary, L, Martin, M, Dneprovskaia, E, Noronha, G, Soll, R, Wrasidlo, W, Acevedo, LM, and Cheresh, DA (2009). Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. J Pharmacol Exp Ther. 328, 758-765.
    CrossRef
  22. Favarin, DC, de Oliveira, JR, de Oliveira, CJ, and de Paula Rogerio, A (2013). Potential effects of medicinal plants and secondary metabolites on acute lung injury. Biomed Res Int. 2013, 576479.
    Pubmed KoreaMed
  23. Fei, XJ, Zhu, LL, Xia, LM, Peng, WB, and Wang, Q (2014). Acanthopanax senticosus attenuates inflammation in lipopolysaccharide-induced acute lung injury by inhibiting the NF-κB pathway. Genet Mol Res. 13, 10537-10544.
    Pubmed CrossRef
  24. Feng, X, and Jia, A (2014). Protective effect of carvacrol on acute lung injury induced by lipopolysaccharide in mice. Inflammation. 37, 1091-1101.
    Pubmed CrossRef
  25. Franciosi, LG, Diamant, Z, Banner, KH, Zuiker, R, Morelli, N, Kamerling, IM, de Kam, ML, Burggraaf, J, Cohen, AF, Cazzola, M, Calzetta, L, Singh, D, Spina, D, Walker, MJ, and Page, CP (2013). Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med. 1, 714-727.
    CrossRef
  26. Freitas, TP, Silveira, PC, Rocha, LG, Rezin, GT, Rocha, J, Citadini-Zanette, V, Romao, PT, Dal-Pizzol, F, Pinho, RA, Andrade, VM, and Streck, EL (2008). Effects of Mikania glomerata Spreng. and Mikania laevigata Schultz Bip. ex Baker (Asteraceae) extracts on pulmonary inflammation and oxidative stress caused by acute coal dust exposure. J. Med. Food. 11, 761-766.
    Pubmed CrossRef
  27. Fu, PK, Yang, CY, Tsai, TH, and Hsieh, CL (2012). Moutan cortex radicis improves lipopolysaccharide-induced acute lung injury in rats through anti-inflammation. Phytomedicine. 19, 1206-1215.
    Pubmed CrossRef
  28. Ganesan, S, Faris, AN, Comstock, AT, Chattoraj, S, Chattoraj, A, Burgess, JR, Curtis, JL, Martinez, FJ, Zick, S, Hershenson, MB, and Sajjan, U (2010). Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression. Respir Res. 11, 131.
    Pubmed KoreaMed CrossRef
  29. Gepdiremen, A, Mshvildadze, V, Süleyman, H, and Elias, R (2005). Acute anti-inflammatory activity of four saponins isolated from ivy: alpha-hederin, hederasaponin-C, hederacolchiside-E and hederacolchiside-F in carrageenan-induced rat paw edema. Phytomedicine. 12, 440-444.
    Pubmed CrossRef
  30. Geraets, L, Haegens, A, Brauers, K, Haydock, JA, Vernoony, JHJ, Wouters, EFM, Bast, A, and Hageman, GJ (2009). Inhibition of LPS-induced pulmonary inflammation by specific flavonoids. Biochem Biophys Res Commun. 382, 598-603.
    Pubmed CrossRef
  31. Gross, D, Shenkman, Z, Bleiberg, B, Dayan, M, Gillelson, M, and Efrat, R (2002). Ginseng improves pulmonary functions and exercise capacity in patients with COPD. Monaldi Arch Chest Dis. 57, 242-246.
  32. Guo, R, Pittier, MH, and Ernst, E (2006). Herbal medicines for the treatment of COPD: a systematic review. Eur Respir J. 28, 330-338.
    Pubmed CrossRef
  33. Ha, HH, Park, SY, Ko, WS, and Kim, YH (2008). Gleditsia sinensis thorns inhibit the production of NO through NF-κB suppression in LPS-stimulated macrophages. J Ethnopharmacol. 118, 429-434.
    Pubmed CrossRef
  34. Han, CW, Kwun, MJ, Kim, KH, Choi, JY, Oh, SR, Ahn, KS, Lee, JH, and Joo, M (2013). Ethanol extract of Alismatis rhizoma reduces acute lung inflammation by suppressing NF-κB and activating Nrf2. J Ethnopharmacol. 146, 402-410.
    Pubmed CrossRef
  35. Hesslinger, C, Strub, A, Boer, R, Ulrich, WR, Lehner, MD, and Braun, C (2009). Inhibition of inducible nitric oxide synthase in respiratory diseases. Biochem Soc Trans. 37, 886-891.
    Pubmed CrossRef
  36. Hocaoglu, AB, Karaman, O, Erge, DO, Erbil, G, Yilmaz, O, Kivcak, B, Bagriyanik, HA, and Uzuner, N (2012). Effect of Hedera helix on lung histopathology in chronic asthma. Iran J Allergy Asthma Immunol. 11, 316-323.
    Pubmed
  37. Hong, E-H, Song, J-H, Shim, A, Lee, B-R, Kwon, B-E, Song, H-H, Kim, Y-J, Chang, S-Y, Jeong, HG, Kim, JG, Seo, S-U, Kim, HP, Kwon, YS, and Ko, H-J (2015a). Coadministration of Hedera helix L. extract enabled mice to overcome insufficient protection against influenza A/PR/8 virus infection under suboptimal treatment with oseltamivir. PLoS ONE. 10, e0131089.
    CrossRef
  38. Hong, JM, Kwon, OK, Shin, IS, Jeon, CM, Shin, NR, Lee, J, Park, SH, Bach, TT, Hai do, V, Oh, SR, Han, SB, and Ahn, KS (2015b). Anti-inflammatory effects of methanol extract of Canarium lyi C.D. Dai & Yakovlev in RAW 264.7 macrophages and a murine model of lipopolysaccharide-induced lung injury. Int J Mol Med. 35, 1403-1410.
  39. Hossein, BM, Nasim, V, and Sediga, A (2008). The protective effect of Nigella sativa on lung injury of sulfur mustard-exposed guinea pigs. Exp Lung Res. 34, 183-194.
    Pubmed CrossRef
  40. Hosseinian, N, Cho, Y, Lockey, RF, and Kolliputi, N (2015). The role of the NLRP3 inflammasome in pulmonary diseases. Ther Adv Respir Dis. 9, 188-197.
    Pubmed CrossRef
  41. Huang, CH, Yang, ML, Tsai, CH, Li, YC, Lin, YJ, and Kuan, YH (2013). Ginkgo biloba leaves extract (EGb761) attenuates lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and NF-κB-dependent matrix metalloproteinase-9 pathway. Phytomedicine. 20, 303-309.
    CrossRef
  42. Huang, GJ, Deng, JS, Chen, CC, Huang, CJ, Sung, PJ, Huang, SS, and Kuo, YH (2014a). Methanol extract of Antrodia camphorata protects against lipopolysaccharide-induced acute lung injury by suppressing NF-κB and MAPK pathways in mice. J Agric Food Chem. 62, 5321-5329.
    CrossRef
  43. Huang, H, Hu, G, Wang, C, Xu, H, Chen, X, and Qian, A (2014b). Cepharanthine, an alkaloid from Stephania cepharantha Hayata, inhibits the inflammatory response in the RAW264.7 cell and mouse models. Inflammation. 37, 235-246.
    CrossRef
  44. Huang, KL, Chen, CS, Hsu, CW, Li, MH, Chang, H, Tsai, SH, and Chu, SJ (2008). Therapeutic effects of baicalin on lipopolysaccharide-induced acute lung injury in rats. Am J Chin Med. 36, 301-311.
    Pubmed CrossRef
  45. Huo, M, Chen, N, Chi, G, Yuan, X, Guan, S, Li, H, Zhong, W, Guo, W, Soromou, LW, Gao, R, Ouyang, H, Deng, X, and Feng, H (2012). Traditional medicine alpinetin inhibits the inflammatory response in Raw 264.7 cells and mouse models. Int Immunopharmacol. 12, 241-248.
    CrossRef
  46. Huo, M, Cui, X, Xue, J, Chi, G, Gao, R, Deng, X, Guan, S, Wei, J, Soromou, LW, Feng, H, and Wang, D (2013a). Anti-inflammatory effects of linalool in RAW 264.7 macrophages and lipopolysaccharide-induced lung injury model. J Surg Res. 180, e47-e54.
    CrossRef
  47. Huo, M, Gao, R, Jiang, L, Cui, X, Duan, L, Deng, X, Guan, S, Wei, J, Soromou, LW, Feng, H, and Chi, G (2013b). Suppression of LPS-induced inflammatory responses by gossypol in RAW 264.7 cells and mouse models. Int Immunopharmacol. 15, 442-449.
    CrossRef
  48. Ilieva, I, Ohgami, K, Shiratori, K, Koyama, Y, Yoshida, K, Kase, S, Kitamei, H, Takemoto, Y, Yazawa, K, and Ohno, S (2004). The effects of Ginkgo biloba extract on lipopolysaccharide-induced inflammation in vitro and in vivo. Exp Eye Res. 79, 181-187.
    Pubmed CrossRef
  49. Jing, W, Chunhua, M, and Shumin, W (2015). Effects of acteoside on lipopolysaccharide-induced inflammation in acute lung injury via regulation of NF-κB pathway in vivo and in vitro. Toxicol Appl Pharmacol. 285, 128-135.
    Pubmed CrossRef
  50. Kao, ST, Liu, CJ, and Yeh, CC (2015). Protective and immunomodulatory effect of flos Lonicerae japonicae by augmenting IL-10 expression in a murine model of acute lung inflammation. J Ethnopharmacol. 168, 108-115.
    Pubmed CrossRef
  51. Kim, J, Cha, YN, and Surh, YJ (2010). A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res. 690, 12-23.
    CrossRef
  52. Kim, SY, Son, KH, Chang, HW, Kang, SS, and Kim, HP (1999). Inhibition of mouse ear edema by steroidal and triterpenoid saponins. Arch Pharm Res. 22, 313-316.
    Pubmed CrossRef
  53. Ko, HJ, Jin, JH, Kwon, OS, Kim, JT, Son, KH, and Kim, HP (2011). Inhibition of experimental lung inflammation and bronchitis by phytoformula containing Broussonetia papyrifera and Lonicera japonica. Biomol. Ther. (Seoul). 19, 324-330.
    CrossRef
  54. Koul, A, Kapoor, N, and Bharati, S (2012). Histopathological, enzymatic, and molecular alterations induced by cigarette smoke inhalation in the pulmonary tissue of mice and its amelioration by aqueous Azadirachta indica leaf extract. J Environ Pathol Toxicol Oncol. 31, 7-15.
    Pubmed CrossRef
  55. Kwak, HG, and Lim, HB (2014). Inhibitory effects of Cnidium monnieri fruit extract on pulmonary inflammation in mice induced by cigarette smoke condensate and lipopolysaccharide. Chin J Nat Med. 12, 641-647.
    Pubmed
  56. Lee, H, Jung, KH, Park, S, Kil, YS, Chung, EY, Jang, YP, Seo, EK, and Bae, H (2014). Inhibitory effects of Stemona tuberosa on lung inflammation in a subacute cigarette smoke-induced mouse model. BMC Complement Altern Med. 14, 513.
    Pubmed KoreaMed CrossRef
  57. Lee, H, Kim, Y, Kim, HJ, Park, S, Jang, YP, Jung, S, Jung, H, and Bae, H (2012). Herbal Formula, PM014, attenuates lung inflammation in a murine model of chronic obstructive pulmonary disease. Evid Based Complement Alternat Med. 2012, 769830.
    Pubmed KoreaMed
  58. Lee, H, Yu, SR, Lim, D, Lee, H, Jin, EY, Jang, YP, and Kim, J (2015a). Galla chinensis attenuates cigarette smoke-associated lung injury by inhibiting recruitment of inflammatory cells into the lung. Basic Clin Pharmacol Toxicol. 116, 222-228.
    CrossRef
  59. Lee, JH, Ahn, J, Kim, JW, Lee, SG, and Kim, HP (2015b). Flavonoids from the aerial parts of Houttuynia cordata attenuate lung inflammation in mice. Arch Pharm Res. 38, 1304-1311.
    CrossRef
  60. Lee, JH, Ko, HJ, Woo, ER, Lee, SK, Moon, BS, Lee, CW, Mandava, S, Samala, M, Lee, J, and Kim, HP (2016). Moracin M inhibits airway inflammation by interrupting the JNK/c-Jun and NF-κB pathways in vitro and in vivo. Eur J Pharmacol. 783, 64-72.
    Pubmed CrossRef
  61. Lee, JH, Lim, HJ, Lee, CW, Son, KH, Son, JK, Lee, SK, and Kim, HP (2015c). Methyl protodioscin from the roots of Asparagus cochinchinensis attenuates airway inflammation by inhibiting cytokine production. Evid Based Complement Alternat Med. 2015, 640846.
    CrossRef
  62. Lee, JP, Li, YC, Chen, HY, Lin, RH, Huang, SS, Chen, HL, Kuan, PC, Liao, MF, Chen, CJ, and Kuan, YH (2010). Protective effects of luteolin against lipopolysaccharide-induced acute lung injury involves inhibition of MEK/ERK and PI3K/Akt pathways in neutrophils. Acta Pharmacol Sin. 31, 831-838.
    Pubmed KoreaMed CrossRef
  63. Lee, JW, Shin, NR, Park, JW, Park, SY, Kwon, OK, Lee, HS, Kim, JH, Lee, HJ, Lee, J, Zhang, ZY, Oh, SR, and Ahn, KS (2015d). Callicarpa japonica Thunb. attenuates cigarette smoke-induced neutrophil inflammation and mucus secretion. J Ethnopharmacol. 175, 1-8.
    CrossRef
  64. Lee, SJ, Shin, EJ, Son, KH, Chang, HW, Kang, SS, and Kim, HP (1995). Anti-inflammatory activity of the major constituents of Lonicera japonica. Arch Pharm Res. 18, 133-135.
    CrossRef
  65. Lee, SJ, Son, KH, Chang, HW, Kang, SS, and Kim, HP (1998). Antiinflammatory activity of Lonicera japonica. Phytother Res. 12, 445-447.
    CrossRef
  66. Li, KC, Ho, YL, Hsieh, WT, Huang, SS, Chang, YS, and Huang, GJ (2015). Apigenin-7-glycoside prevents LPS-induced acute lung injury via downregulation of oxidative enzyme expression and protein activation through inhibition of MAPK phosphorylation. Int J Mol Sci. 16, 1736-1754.
    Pubmed KoreaMed CrossRef
  67. Li, L, Bao, H, Wu, J, Duan, X, Liu, B, Sun, J, Gong, W, Lv, Y, Zhang, H, Luo, Q, Wu, X, and Dong, J (2012a). Baicalin is anti-inflammatory in cigarette smoke-induced inflammatory models in vivo and in vitro: A possible role for HDAC2 activity. Int Immunopharmacol. 13, 15-22.
    CrossRef
  68. Li, W, Xie, JY, Li, H, Zhang, YY, Cao, J, Cheng, ZH, and Chen, DF (2012b). Viola yedoensis liposoluble fraction ameliorates lipopolysaccharide-induced acute lung injury in mice. Am J Chin Med. 40, 1007-1018.
    CrossRef
  69. Lim, HJ, Jin, HG, Woo, ER, Lee, SK, and Kim, HP (2013). The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation. J Ethnopharmacol. 149, 169-175.
    Pubmed CrossRef
  70. Lim, HJ, Lee, JH, Choi, JS, Lee, SK, Kim, YS, and Kim, HP (2014). Inhibition of airway inflammation by the roots of Angelica decursiva and its constituent, columbianadin. J Ethnopharmacol. 155, 1353-1361.
    Pubmed CrossRef
  71. Lim, J-C, Park, JH, Budensinsky, M, Kasal, A, Han, Y-H, Koo, B-S, Lee, S-I, and Lee, D-U (2005). Antimutagenic constituents from the thorns of Gleditsia sinensis. Chem Pharm Bull. 53, 561-564.
    Pubmed CrossRef
  72. Liu, H, Ren, J, Chen, H, Huang, Y, Li, H, Zhang, Z, and Wang, J (2014a). Resveratrol protects against cigarette smoke-induced oxidative damage and pulmonary inflammation. J Biochem Mol Toxicol. 28, 465-471.
    CrossRef
  73. Liu, L, Xiong, H, Ping, J, Ju, Y, and Zhang, X (2010). Taraxacum officinale protects against lipopolysaccharide-induced acute lung injury in mice. J Ethnopharmacol. 130, 392-397.
    Pubmed CrossRef
  74. Liu, MH, Lin, AH, Lee, HF, Ko, HK, Lee, TS, and Kou, YR (2014b). Paeonol attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling. Mediators Inflamm. 2014, 651890.
    CrossRef
  75. Lyu, JH, Kim, KH, Kim, HW, Cho, SI, Ha, KT, Choi, JY, Han, CW, Jeong, HS, Lee, HK, Ahn, KS, Oh, SR, Sadikot, RT, Christman, JW, and Joo, M (2012). Dangkwisoo-san, an herbal medicinal formula, ameliorates acute lung inflammation via activation of Nrf2 and suppression of NF-κB. J Ethnopharmacol. 140, 107-116.
    Pubmed KoreaMed CrossRef
  76. Ma, C, Zhu, L, Wang, J, He, H, Chang, X, Gao, J, Shumin, W, and Yan, T (2015a). Anti-inflammatory effects of water extract of Taraxacum mongolicum hand.-Mazz on lipopolysaccharide-induced inflammation in acute lung injury by suppressing PI3K/Akt/mTOR signaling pathway. J Ethnopharmacol. 168, 349-355.
    CrossRef
  77. Ma, CH, Liu, JP, Qu, R, and Ma, SP (2014). Tectorigenin inhibits the inflammation of LPS-induced acute lung injury in mice. Chin J Nat Med. 12, 841-846.
    Pubmed
  78. Ma, J, Xu, H, Wu, J, Qu, C, Sun, F, and Xu, S (2015b). Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation. Int Immunopharmacol. 29, 708-713.
    CrossRef
  79. Mahler, DA, Huang, S, Tabrizi, M, and Bell, GM (2004). Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest. 126, 926-934.
    Pubmed CrossRef
  80. Mao, YF, Li, YQ, Zong, L, You, XM, Lin, FQ, and Jiang, L (2010). Methanol extract of Phellodendri cortex alleviates lipopolysaccharide-induced acute airway inflammation in mice. Immunopharmacol Immunotoxicol. 32, 110-115.
    CrossRef
  81. Marks-Konczalik, J, Costa, M, Robertson, J, McKie, E, Yang, S, and Pascoe, S (2015). A post-hoc subgroup analysis of data from a six month clinical trial comparing the efficacy and safety of losmapimod in moderate-severe COPD patients with ≤2% and >2% blood eosinophils. Respir Med. 109, 860-869.
    Pubmed CrossRef
  82. Matthys, H, and Funk, P (2008). EPs 7630 improves acute bronchitic symptoms and shortens time to remission. Results of a randomised, double-blind, placebo-controlled, multicentre trial. Planta Med. 74, 686-692.
    Pubmed CrossRef
  83. Matute-Bello, G, Frevert, CW, and Martin, TR (2008). Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 295, L379-L399.
    Pubmed KoreaMed CrossRef
  84. Moretto, N, Caruso, P, Bosco, R, Marchini, G, Pastore, F, Armani, E, Amari, G, Rizzi, A, Ghidini, E, De Fanti, R, Capaldi, C, Carzaniga, L, Hirsch, E, Buccellati, C, Sala, A, Carnini, C, Patacchini, R, Delcanale, M, Civelli, M, Villetti, G, and Facchinetti, F (2015). CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration. J Pharmacol Exp Ther. 352, 559-567.
    Pubmed CrossRef
  85. Morris, A, Kinnear, G, Wan, WY, Wyss, D, Bahra, P, and Stevenson, CS (2008). Comparison of cigarette smoke-induced acute inflammation in multiple strains of mice and the effect of a matrix metalloproteinase inhibitor on these responses. J Pharmacol Exp Ther. 327, 851-862.
    Pubmed CrossRef
  86. Moura, RS, Ferreira, TS, Lopes, AA, Pires, KM, Nesi, RT, Resende, AC, Souza, PJ, Silva, AJ, Borges, RM, Porto, LC, and Valenca, SS (2012). Effects of Euterpe oleracea Mart. (AçAÍ) extract in acute lung inflammation induced by cigarette smoke in the mouse. Phytomedicine. 19, 262-269.
    CrossRef
  87. Muntuschi, P, Kharitonov, SA, Ciabattoni, G, and Barnes, PJ (2003). Exhaled leukotrienes and prostaglandins in COPD. Thorax. 58, 585-588.
    CrossRef
  88. Nie, YC, Wu, H, Li, PB, Luo, YL, Long, K, Xie, LM, Shen, JG, and Su, WW (2012). Anti-inflammatory effects of naringin in chronic pulmonary neutrophilic inflammation in cigarette smoke-exposed rats. J. Med. Food. 15, 894-900.
    Pubmed CrossRef
  89. Noh, S, Ahn, KS, Oh, SR, Kim, KH, and Joo, M (2015). Neutrophilic lung inflammation suppressed by picroside II is associated with TGF-β signaling. Evid Based Complement Alternat Med. 2015, 897272.
    CrossRef
  90. Nomura, T (2001). Chemistry and biosynthesis of prenylflavonoids. Yakugaku Zasshi. 121, 535-556.
    Pubmed CrossRef
  91. Norman, P (2013). Evidence on the identity of the CXCR2 antagonist AZD-5069. Expert Opin Ther Pat. 23, 113-117.
    CrossRef
  92. Norman, P (2015). Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert Opin. Investig. Drugs. 24, 383-392.
    Pubmed CrossRef
  93. Pinner, NA, Hamilton, LA, and Hughes, A (2012). Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. Clin Ther. 34, 56-66.
    Pubmed CrossRef
  94. Qamar, W, and Sultana, S (2011). Polyphenols from Juglans regia L. (walnut) kernel modulate cigarette smoke extract induced acute inflammation, oxidative stress and lung injury in Wistar rats. Hum Exp Toxicol. 30, 499-506.
    CrossRef
  95. Qiu, J, Chi, G, Wu, Q, Ren, Y, Chen, C, and Feng, H (2016). Pretreatment with the compound asperuloside decreases acute lung injury via inhibiting MAPK and NF-κB signaling in a murine model. Int Immunopharmacol. 31, 109-115.
    CrossRef
  96. Rastrick, JM, Stevenson, CS, Eltom, S, Grace, M, Davies, M, Kilty, I, Evans, SM, Pasparakis, M, Catley, MC, Lawrence, T, Adcock, IM, Belvisi, MG, and Birrell, MA (2013). Cigarette smoke induced airway inflammation is independent of NF-κB signalling. PLoS ONE. 8, e54128.
    CrossRef
  97. Reid, DJ, and Pham, NT (2012). Roflumilast: a novel treatment for chronic pulmonary disease. Ann Pharmacother. 46, 521-529.
    Pubmed CrossRef
  98. Rennard, SI, Dale, DC, Donohue, JF, Kanniess, F, Magnussen, H, Sutherland, ER, Watz, H, Lu, S, Stryszak, P, Rosenberg, E, and Staudinger, H (2015). CXCR2 Antagonist MK-7123. A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 191, 1001-1011.
    Pubmed CrossRef
  99. Ribeiro, A, Ferraz-Paula, V, Pinheiro, ML, Vitoretti, LB, Mariano-Souza, DP, Quinteiro-Filho, WM, Akamine, AT, Almeida, VI, Quevedo, J, Dal-Pizzol, F, Hallak, JE, Zuardi, AW, Crippa, JA, and Palermo-Neto, J (2012). Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor. Eur J Pharmacol. 678, 78-85.
    Pubmed CrossRef
  100. Rojas, M, Woods, CR, Mora, AL, Xu, J, and Brigham, KL (2005). Endotoxin-induced lung injury in mice: structural, functional, and biochemical responses. Am J Physiol Lung Cell Mol Physiol. 288, L333-L341.
    CrossRef
  101. Rovina, N, Dima, E, Gerassimou, C, Kollintza, A, Gratziou, C, and Roussos, C (2009). Interleukin-18 in induced sputum: association with lung function in chronic obstructive pulmonary disease. Respir Med. 103, 1056-1062.
    Pubmed CrossRef
  102. San, Z, Fu, Y, Li, W, Zhou, E, Li, Y, Song, X, Wang, T, Tian, Y, Wei, Z, Yao, M, Cao, Y, and Zhang, N (2014). Protective effect of taraxasterol on acute lung injury induced by lipopolysaccharide in mice. Int Immunopharmacol. 19, 342-350.
    Pubmed CrossRef
  103. Santana, FP, Pinheiro, NM, Mernak, MI, Righetti, RF, Martins, MA, Lago, JH, Lopes, FD, Tiberio, IF, and Prado, CM (2016). Evidence of herbal medicine-derived natural products effects in inflammatory lung diseases. Mediators Inflamm. 2016, 2348968.
    CrossRef
  104. Schuliga, M (2015). NF-kappaB signaling in chronic inflammatory airway disease. Biomolecules. 5, 1266-1283.
    Pubmed KoreaMed CrossRef
  105. Seimetz, M, Parajuli, N, Pichl, A, Veit, F, Kwapiszewska, G, Weisel, FC, Milger, K, Egemnazarov, B, Turowska, A, Fuchs, B, Nikam, S, Roth, M, Sydykov, A, Medebach, T, Klepetko, W, Jaksch, P, Dumitrascu, R, Garn, H, Voswinckel, R, Kostin, S, Seeger, W, Schermuly, RT, Grimminger, F, Ghofrani, HA, and Weissmann, N (2011). Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell. 147, 293-305.
    Pubmed CrossRef
  106. Sezer, M, Sahin, O, Solak, O, Fidan, F, Kara, Z, and Unlu, M (2007). Effects of caffeic acid phenethyl ester on the histopathological changes in the lungs of cigarette smoke-exposed rabbits. Basic Clin Pharmacol Toxicol. 101, 187-191.
    Pubmed CrossRef
  107. Sharafkhaneh, A, Velamuri, S, Badmaev, V, Lan, C, and Hanania, N (2007). The potential role of natural agents in treatment of airway inflammation. Ther Adv Respir Dis. 1, 105-120.
    CrossRef
  108. Sharma, M, Arnason, JT, Burt, A, and Hudson, JB (2006). Echinacea extracts modulate the pattern of chemokine and cytokine secretion in rhinovirus-infected and uninfected epithelial cells. Phytother Res. 20, 147-152.
    Pubmed CrossRef
  109. Shi, D, Zheng, M, Wang, Y, Liu, C, and Chen, S (2014). Protective effects and mechanisms of mogroside V on LPS-induced acute lung injury in mice. Pharm Biol. 52, 729-734.
    Pubmed CrossRef
  110. Shim, DW, Han, JW, Sun, X, Jang, CH, Koppula, S, Kim, TJ, Kang, TB, and Lee, KH (2013). Lysimachia clethroides Duby extract attenuates inflammatory response in Raw 264.7 macrophages stimulated with lipopolysaccharide and in acute lung injury mouse model. J Ethnopharmacol. 150, 1007-1015.
    Pubmed CrossRef
  111. Soromou, LW, Chu, X, Jiang, L, Wei, M, Huo, M, Chen, N, Guan, N, Yang, X, Chen, C, Feng, H, and Deng, X (2012). In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses. Int Immunopharmacol. 14, 66-74.
    Pubmed CrossRef
  112. Sriskantharajah, S, Hamblin, N, Worsley, S, Calver, AR, Hessel, EM, and Amour, A (2013). Targeting phosphoinositide 3-kinase δ for the treatment of respiratory diseases. Ann N Y Acad Sci. 1280, 35-39.
    Pubmed CrossRef
  113. , (2000). Pharmacopoeia of the People’s Republic of China. Beijing: Chemical Industry Press, pp. 225-226
  114. Stolk, J, Rossie, W, and Dijkman, JH (1994). Apocynin improves the efficacy of secretory leukocyte protease inhibitor in experimental emphysema. Am J Respir Crit Care Med. 150, 1628-1631.
    Pubmed CrossRef
  115. Su, ZQ, Mo, ZZ, Liao, JB, Feng, XX, Liang, YZ, Zhang, X, Liu, YH, Chen, XY, Chen, ZW, Su, ZR, and Lai, XP (2014). Usnic acid protects LPS-induced acute lung injury in mice through attenuating inflammatory responses and oxidative stress. Int Immunopharmacol. 22, 371-378.
    Pubmed CrossRef
  116. Sun, J, Chi, G, Soromou, LW, Chen, N, Guan, M, Wu, Q, Wang, D, and Li, H (2012). Preventive effect of imperatorin on acute lung injury induced by lipopolysaccharide in mice. Int Immunopharmacol. 14, 369-374.
    Pubmed CrossRef
  117. Taguchi, L, Pinheiro, NM, Olivo, CR, Choqueta-Toledo, A, Grecco, SS, Lopes, FD, Caperuto, LC, Martins, MA, Tiberio, IF, Camara, NO, Lago, JH, and Prado, CM (2015). A flavanone from Baccharis retusa (Asteraceae) prevents elastase-induced emphysema in mice by regulating NF-κB, oxidative stress and metalloproteinases. Respir Res. 16, 79.
    CrossRef
  118. Tajima, S, Bando, M, Yamasawa, H, Ohno, S, Moriyama, H, Takada, T, Suzuki, E, Geiyo, F, and Sigiyama, Y (2006). Preventive effect of Hochu-ekki-to on lipopolysaccharide-induced acute lung injury in BALB/c mice. Lung. 184, 318-323.
    Pubmed CrossRef
  119. Tao, W, Su, Q, Wang, H, Guo, S, Chen, Y, Duan, J, and Wang, S (2015). Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro. Int Immunopharmacol. 27, 138-147.
    Pubmed CrossRef
  120. Tianzhu, Z, Shihai, Y, and Juan, D (2014). The effects of morin on lipopolysaccharide-induced acute lung injury by suppressing the lung NLRP3 inflammasome. Inflammation. 37, 1976-1983.
    Pubmed CrossRef
  121. Tianzhu, Z, and Shumin, W (2015). Esculin inhibits the inflammation of LPS-induced acute lung injury in mice via regulation of TLR/NF-κB pathways. Inflammation. 38, 1529-1536.
    Pubmed CrossRef
  122. To, Y, Ito, K, Kizawa, Y, Failla, M, Ito, M, Kusama, T, Elliott, WM, Hogg, JC, Adcock, IM, and Barnes, PJ (2010). Targeting phosphoinositide-3-kinase-δ with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 182, 897-904.
    Pubmed KoreaMed CrossRef
  123. Tsai, CL, Lin, YC, Wang, HM, and Chou, TC (2014). Baicalein, an active component of Scutellaria baicalensis, protects against lipopolysaccharide-induced acute lung injury in rats. J Ethnopharmacol. 153, 197-206.
    Pubmed CrossRef
  124. Wang, J, Nie, Y, Li, Y, Hou, Y, Zhao, W, Deng, J, Wang, PG, and Bai, G (2015). Identification of target proteins of mangiferin in mice with acute lung injury using functionalized magnetic microspheres based on click chemistry. J Agric Food Chem. 63, 10013-10021.
    Pubmed CrossRef
  125. Watz, H, Barnacle, H, Hartley, BF, and Chan, R (2014). Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med. 2, 63-72.
    Pubmed CrossRef
  126. Wei, D, and Huang, Z (2014). Anti-inflammatory effects of triptolide in LPS-induced acute lung injury in mice. Inflammation. 37, 1307-1316.
    Pubmed CrossRef
  127. Wei, M, Chu, X, Jiang, L, Yang, X, Cai, Q, Zheng, C, Ci, X, Guan, M, Liu, J, and Deng, X (2012). Protocatechuic acid attenuates lipopolysaccharide-induced acute lung injury. Inflammation. 35, 1169-1178.
    Pubmed CrossRef
  128. Wright, JL, Cosio, M, and Churg, A (2008). Animal models of chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 295, L1-L15.
    Pubmed KoreaMed CrossRef
  129. Wu, G, Du, L, Zhao, L, Shang, R, Liu, D, Jing, Q, Liang, J, and Ren, Y (2014a). The total alkaloids of Aconitum tanguticum protect against lipopolysaccharide-induced acute lung injury in rats. J Ethnopharmacol. 155, 1483-1491.
    CrossRef
  130. Wu, XL, Feng, XX, Li, CW, Zhang, XJ, Chen, ZW, Chen, JN, Lai, XP, Zhang, SX, Li, YC, and Su, ZR (2014b). The protective effects of the supercritical-carbon dioxide fluid extract of Chrysanthemum indicum against lipopolysaccharide-induced acute lung injury in mice via modulating Toll-like receptor 4 signaling pathway. Mediators Inflamm. 2014, 246407.
    CrossRef
  131. Xie, G, Chen, N, Soromou, LW, Liu, F, Xiong, Y, Wu, Q, Li, H, Feng, H, and Liu, G (2012). p-Cymene protects mice against lipopolysaccharide-induced acute lung injury by inhibiting inflammatory cell activation. Molecules. 17, 8159-8173.
    Pubmed CrossRef
  132. Xie, X, Sun, S, Zhong, W, Soromou, LW, Zhou, X, Wei, M, Ren, Y, and Ding, Y (2014). Zingerone attenuates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol. 19, 103-109.
    Pubmed CrossRef
  133. Xie, YC, Dong, XW, Wu, XM, Yan, XF, and Xie, QM (2009). Inhibitory effects of flavonoids extracted from licorice on lipopolysaccharide-induced acute pulmonary inflammation in mice. Int Immunopharmacol. 9, 194-200.
    CrossRef
  134. Xu, D, Wan, C, Wang, T, Tian, P, Li, D, Wu, Y, Fan, S, Chen, L, Shen, Y, and Wen, F (2015). Berberine attenuates cigarette smoke-induced airway inflammation and mucus hypersecretion in mice. Int J Clin Exp Med. 8, 8641-8647.
    Pubmed KoreaMed
  135. Yang, D, Zhang, W, Song, L, and Guo, F (2013). Andrographolide protects against cigarette smoke-induced lung inflammation through activation of heme oxygenase-1. J Biochem Mol Toxicol. 27, 259-265.
    Pubmed CrossRef
  136. Yang, T, Luo, F, Shen, Y, An, J, Li, X, Liu, X, Ying, B, Liao, Z, Dong, J, Guo, L, Wang, T, Xu, D, Chen, L, and Wen, F (2012). Quercetin attenuates airway inflammation and mucus production induced by cigarette smoke in rats. Int Immunopharmacol. 13, 73-81.
    Pubmed CrossRef
  137. Yeh, CC, Kao, SJ, Lin, CC, Wang, SD, Liu, CJ, and Kao, ST (2007a). The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro. Life Sci. 80, 1821-1831.
    CrossRef
  138. Yeh, CC, Lin, CC, Wang, SD, Chen, YS, Su, BH, and Kao, ST (2006). Protective and anti-inflammatory effect of a traditional Chinese medicine, Xia-Bai-San, by modulating lung local cytokine in a murine model of acute lung injury. Int Immunopharmacol. 6, 1506-1514.
    Pubmed CrossRef
  139. Yeh, CC, Lin, CC, Wang, SD, Hung, CM, Yeh, MH, Liu, CJ, and Kao, ST (2007b). Protective and immunomodulatory effect of Gingyo-san in a murine model of acute lung inflammation. J Ethnopharmacol. 111, 418-426.
    CrossRef
  140. Yingkun, N, Zhenyu, W, Jing, L, Xinyun, L, and Huimin, Y (2013). Stevioside protects LPS-induced acute lung injury in mice. Inflammation. 36, 242-250.
    CrossRef
  141. Yu, JL, Zhang, XS, Xue, X, and Wang, RM (2015). Patchouli alcohol protects against lipopolysaccharide-induced acute lung injury in mice. J Surg Res. 194, 537-543.
    CrossRef
  142. Zhang, H (2011). Anti-IL-1β therapies. Recent Pat DNA Gene Seq. 5, 126-135.
    Pubmed CrossRef
  143. Zhang, SY, Xu, LT, Li, AX, and Wang, SM (2015). Effects of ergosterol, isolated from Scleroderma polyrhizum Pers., on lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation. 38, 1979-1985.
    Pubmed CrossRef
  144. Zhao, YL, Shang, JH, Pu, SB, Wang, HS, Wang, B, Liu, L, Liu, YP, Shen, HM, and Luo, XD (2016). Effect of total alkaloids from Alstonia scholaris on airway inflammation in rats. J Ethnopharmacol. 178, 258-265.
    CrossRef
  145. Zhong, S, Nie, YC, Gan, ZY, Liu, XD, Fang, ZF, Zhong, BN, Tian, J, Huang, CQ, Lai, KF, and Zhong, NS (2015). Effects of Schisandra chinensis extracts on cough and pulmonary inflammation in a cough hypersensitivity guinea pig model induced by cigarette smoke exposure. J Ethnopharmacol. 165, 73-82.
    Pubmed CrossRef
  146. Zhong, WT, Jiang, LX, Wei, JY, Qiao, AN, Wei, MM, Soromou, LW, Xie, XX, Zhou, X, Ci, XX, and Wang, DC (2013a). Protective effect of esculentoside A on lipopolysaccharide-induced acute lung injury in mice. J Surg Res. 185, 364-372.
    CrossRef
  147. Zhong, WT, Wu, YC, Xie, XX, Zhou, X, Wei, MM, Soromou, LW, Ci, XX, and Wang, DC (2013b). Phillyrin attenuates LPS-induced pulmonary inflammation via suppression of MAPK and NF-κB activation in acute lung injury mice. Fitoterapia. 90, 132-139.
    CrossRef
  148. Zhou, E, Li, Y, Wei, Z, Fu, Y, Lei, H, Zhang, N, Yang, Z, and Xie, GS (2014). Schisantherin A protects lipopolysaccharide-induced acute respiratory distress syndrome in mice through inhibiting NF-κB and MAPKs signaling pathways. Int Immunopharmacol. 22, 133-140.
    Pubmed CrossRef
  149. Zhu, GF, Guo, HJ, Huang, Y, Wu, CT, and Zhang, XF (2015). Eriodictyol, a plant flavonoid, attenuates LPS-induced acute lung injury through its antioxidant and anti-inflammatory activity. Exp Ther Med. 10, 2259-2266.
    Pubmed KoreaMed


This Article


Cited By Articles
  • CrossRef (0)

Funding Information

Services
Social Network Service

e-submission

Archives