Aesculetin Attenuates Alveolar Injury and Fibrosis Induced by Close Contact of Alveolar Epithelial Cells with Blood-Derived Macrophages via IL-8 Signaling

Pulmonary fibrosis is a disease in which lung tissues become fibrous and thereby causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract, secreting inflammatory cytokines, which subsequently leads to the development of pulmonary fibrosis. Aesculetin, a major component of the sancho tree and chicory, is known to biologically have antioxidant and anti-inflammatory effects. Human alveolar epithelial A549 cells were cultured for 24 h in conditioned media of THP-1 monocyte-derived macrophages (mCM) with 1–20 μM aesculetin. Micromolar aesculetin attenuated the cytotoxicity of mCM containing inflammatory tumor necrosis factor-α (TNF)-α and interleukin (IL)-8 as major cytokines. Aesculetin inhibited alveolar epithelial induction of the mesenchymal markers in mCM-exposed/IL-8-loaded A549 cells (≈47–51% inhibition), while epithelial markers were induced in aesculetin-treated cells subject to mCM/IL-8 (≈1.5–2.3-fold induction). Aesculetin added to mCM-stimulated A549 cells abrogated the collagen production and alveolar epithelial CXC-chemokine receptor 2 (CXCR2) induction. The production of matrix metalloproteinase (MMP) proteins in mCM-loaded A549 cells was reduced by aesculetin (≈52% reduction), in parallel with its increase in tissue inhibitor of metalloproteinases (TIMP) proteins (≈1.8-fold increase). In addition, aesculetin enhanced epithelial induction of tight junction proteins in mCM-/IL-8-exposed cells (≈2.3–2.5-fold induction). The inhalation of polyhexamethylene guanidine (PHMG) in mice accompanied neutrophil predominance in bronchoalveolar lavage fluid (BALF) and macrophage infiltration in alveoli, which was inhibited by orally administrating aesculetin to mice. Treating aesculetin to mice alleviated PHMG-induced IL-8-mediated subepithelial fibrosis and airway barrier disruption. Taken together, aesculetin may antagonize pulmonary fibrosis and alveolar epithelial barrier disruption stimulated by the infiltration of monocyte-derived macrophages, which is typical of PHMG toxicity, involving interaction of IL-8 and CXCR2. Aesculetin maybe a promising agent counteracting macrophage-mediated inflammation-associated pulmonary disorders.

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Idebenone has preventative and therapeutic effects on pulmonary fibrosis via preferential suppression of fibroblast activity

Cell Death Discovery ◽

10.1038/s41420-019-0226-y ◽

2019 ◽

Vol 5 (1) ◽

Author(s):

Toshifumi Sugizaki ◽

Ken-ichiro Tanaka ◽

Teita Asano ◽

Daisuke Kobayashi ◽

Yuuki Hino ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Lung Fibroblasts ◽

Epithelial Cell Line ◽

Therapeutic Effects ◽

Synthetic Analogue ◽

Apoptosis Resistance ◽

Collagen Production ◽

Alveolar Epithelial

AbstractAlveolar epithelial injury induced by reactive oxygen species (ROS) and abnormal collagen production by activated fibroblasts (myofibroblasts) is involved in the onset and exacerbation of idiopathic pulmonary fibrosis (IPF). Compared with alveolar epithelial cells, lung fibroblasts, especially myofibroblasts, exhibit an apoptosis-resistance phenotype (apoptosis paradox) that appears to be involved in IPF pathogenesis. Thus, we screened for chemicals eliciting preferential cytotoxicity of LL29 cells (lung fibroblasts from an IPF patient) compared with A549 cells (human lung alveolar epithelial cell line) from medicines already in clinical use. We identified idebenone, a synthetic analogue of coenzyme Q10 (CoQ10, an antioxidant) that has been used clinically as a brain metabolic stimulant. Idebenone induced cell growth inhibition and cell death in LL29 cells at a lower concentration than in A549 cells, a feature that was not observed for other antioxidant molecules (such as CoQ10) and two IPF drugs (pirfenidone and nintedanib). Administration of idebenone prevented bleomycin-induced pulmonary fibrosis and increased pulmonary ROS levels. Importantly, idebenone also improved pulmonary fibrosis and lung function when administered after the development of fibrosis, whereas administration of CoQ10 similarly prevented bleomycin-induced pulmonary fibrosis, but had no effect after its development. Administration of idebenone, but not CoQ10, suppressed bleomycin-induced increases in lung myofibroblasts. In vitro, treatment of LL29 cells with idebenone, but not CoQ10, suppressed TGF-β–induced collagen production. These results suggest that in addition to antioxidant activity, idebenone exerts inhibitory activity on the function of lung fibroblasts, with the former activity being preventative and the latter therapeutic for bleomycin-induced fibrosis. Thus, we propose that idebenone may be more therapeutically beneficial for IPF patients than current treatments.

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Aesculetin Attenuates Pulmonary Fibrosis Induced by Close Contact of Macrophages with Alveolar Epithelial Cells

Current Developments in Nutrition ◽

10.1093/cdn/nzaa068_016 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1531-1531

Author(s):

Suyeon Oh ◽

Young-Hee Kang

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

A549 Cells ◽

Conditioned Media ◽

Alveolar Epithelial Cells ◽

Alveolar Cells ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Funding Sources ◽

E Cadherin

Abstract Objectives Pulmonary fibrosis is a disease in which lung tissues become fibrous and causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract. These macrophages secrete various inflammatory cytokines leading to development of pulmonary fibrosis via epithelial–mesenchymal transition (EMT) process. Aesculetin, a major component of Sancho tree and Chicory, is known to have antioxidant and anti-inflammatory effects in the vascular and immune system. Methods Human alveolar basal epithelial A549 cells were cultured in conditioned media of THP-1 monocyte-derived macrophages for 24 h. Aesculetin at the concentrations of 1–20 μM did not show cytotoxicity of A549 cells. Alveolar epithelial cells were incubated with interleukin (IL)-8. Western blotting examined EMT-associated fibrotic proteins from A549 cell lysates. Matrix metalloproteinase (MMP) activity was measured with gelatin zymography. In addition, inflammation- and fibrosis-related cytokines were measured by using ELISA kits. Results The epithelial markers of E-cadherin and ZO-1 were reduced in cells exposed to macrophage-conditioned media containing IL-8 and TNF-α. Macrophage-conditioned media enhanced expression of the mesenchymal fibrotic markers of α-smooth muscle actin (α-SMA), vimentin and fibronectin, and the fibrotic proteins of collagen I and collagen IV were enhanced. However, ≥10 μM aesculetin reciprocally manipulated the expression levels of these proteins of A549 cells. In addition, macrophage-conditioned media enhanced the expression and activity of MT1-MMP, MMP-2 and MMP-9. In contrast, the expression of tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 were reduced by exposure of alveolar cells to conditioned media. Proinflammatory and chemotactic IL-8 reduced E-cadherin and conversely enhanced N-cadherin and α-SMA in A549 cells, which was reciprocally modulated by ≥ 10 μM aesculetin. These results demonstrate that aesculetin may ameliorate EMT-associated pulmonary fibrosis caused by contact of blood-derived macrophages and alveolar cells. Conclusions Aesculetin maybe a promising agent treating progressive pulmonary disorders owing to macrophage-mediated inflammation. Funding Sources No funding sources to report.

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The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.642855 ◽

2021 ◽

Vol 12 ◽

Author(s):

Benedikt Jäger ◽

Benjamin Seeliger ◽

Oliver Terwolbeck ◽

Gregor Warnecke ◽

Tobias Welte ◽

...

Keyword(s):

Epithelial Cells ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Nlrp3 Inflammasome ◽

Cathepsin B ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial ◽

Caspase 1 ◽

Acute Exacerbations

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease harboring significant morbidity and mortality despite recent advances in therapy. Regardless of disease severity acute exacerbations (IPF-AEs) may occur leading to considerable loss of function and are the leading cause of death in IPF. Histologic features of IPF-AE are very similar to acute respiratory distress syndrome (ARDS), but the underlying mechanisms are incompletely understood. We investigated the role of the NLRP3 inflammasome in IPF and IPF-AE. Bronchoalveolar lavage (BAL) cells were sampled from patients with IPF (n = 32), IPF-AE (n = 10), ARDS (n = 7) and healthy volunteers (HV, n = 37) and the NLRP3-inflammasome was stimulated in-vitro. We found the NLRP3 inflammasome to be hyper-inducible in IPF compared to HV with increased IL-1ß and pro-IL-1ß levels on ELISA upon stimulation as well as increased caspase-1 activity measured by caspase-1p20 immunoblotting. In IPF-AE, IL-1ß was massively elevated to an extent similar to ARDS. To evaluate potential mechanisms, we co-cultured BAL cells with radiated A549 cells (a model to simulate apoptotic alveolar epithelial cells), which led to increased NLRP3 mRNA expression and increased caspase-1 dependent IL-1ß production. In the presence of a reactive oxygen species (ROS) inhibitor (diphenyleneiodonium) and a cathepsin B inhibitor (E64D), NLRP3 expression was suppressed indicating that induction of NLRP3 activation following efferocytosis of apoptotic A549 cells is mediated via ROS and cathepsin-B. In summary, we present evidence of involvement of the NLRP3 inflammasome-caspase pathway in the pathogenesis of IPF-AE, similarly to ARDS, which may be mediated by efferocytosis of apoptotic alveolar epithelial cells in IPF.

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Atractylodin Suppresses TGF-β-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms222011152 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11152

Author(s):

Kai-Wei Chang ◽

Xiang Zhang ◽

Shih-Chao Lin ◽

Yu-Chao Lin ◽

Chia-Hsiang Li ◽

...

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Epithelial Mesenchymal Transition ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Collagen Deposition ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic change in alveolar epithelial cells and leads to the irreversible deterioration of pulmonary function. Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells contributes to excessive collagen deposition and plays an important role in IPF. Atractylodin (ATL) is a kind of herbal medicine that has been proven to protect intestinal inflammation and attenuate acute lung injury. Our study aimed to determine whether EMT played a crucial role in the pathogenesis of pulmonary fibrosis and whether EMT can be utilized as a therapeutic target by ATL treatment to mitigate IPF. To address this topic, we took two steps to investigate: 1. Utilization of anin vitro EMT model by treating alveolar epithelial cells (A549 cells) with TGF-β1 followed by ATL treatment for elucidating the underlying pathways, including Smad2/3 hyperphosphorylation, mitogen-activated protein kinase (MAPK) pathway overexpression, Snail and Slug upregulation, and loss of E-cadherin. Utilization of an in vivo lung injury model by treating bleomycin on mice followed by ATL treatment to demonstrate the therapeutic effectiveness, such as, less collagen deposition and lower E-cadherin expression. In conclusion, ATL attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in mice.

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YY1 mediates TGF-β1-induced EMT and pro-fibrogenesis in alveolar epithelial cells

Respiratory Research ◽

10.1186/s12931-019-1223-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 12

Author(s):

Chuyi Zhang ◽

Xiaoping Zhu ◽

Yifei Hua ◽

Qian Zhao ◽

Kaijing Wang ◽

...

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Lung Epithelial Cells ◽

Lung Damage ◽

Type Ii ◽

Mesenchymal Transition ◽

Alveolar Epithelial

Abstract Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring. The pathological mechanism causing pulmonary fibrosis remains unknown. Emerging evidence suggests prominent roles of epithelial–mesenchymal transition (EMT) of alveolar epithelial cells (AECs) in myofibroblast formation and progressive pulmonary fibrosis. Our previous work has demonstrated the regulation of YY1 in idiopathic pulmonary fibrosis and pathogenesis of fibroid lung. However, the specific function of YY1 in AECs during the pathogenesis of pulmonary fibrosis is yet to be determined. Herein, we found the higher level of YY1 in primary fibroblasts than that in primary epithelial cells from the lung of mouse. A549 and BEAS-2B cells, serving as models for type II alveolar pulmonary epithelium in vitro, were used to determine the function of YY1 during EMT of AECs. TGF-β-induced activation of the pro-fibrotic program was applied to determine the role YY1 may play in pro-fibrogenesis of type II alveolar epithelial cells. Upregulation of YY1 was associated with EMT and pro-fibrotic phenotype induced by TGF-β treatment. Targeted knockdown of YY1 abrogated the EMT induction by TGF-β treatment. Enforced expression of YY1 can partly mimic the TGF-β-induced pro-fibrotic change in either A549 cell line or primary alveolar epithelial cells, indicating the induction of YY1 expression may mediate the TGF-β-induced EMT and pro-fibrosis. In addition, the translocation of NF-κB p65 from the cytoplasm to the nucleus was demonstrated in A549 cells after TGF-β treatment and/or YY1 overexpression, suggesting that NF-κB-YY1 signaling pathway regulates pulmonary fibrotic progression in lung epithelial cells. These findings will shed light on the better understanding of mechanisms regulating pro-fibrogenesis in AECs and pathogenesis of lung fibrosis.

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Modulation of α-ENaC and α1-Na+-K+-ATPase by cAMP and dexamethasone in alveolar epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.281.1.l217 ◽

2001 ◽

Vol 281 (1) ◽

pp. L217-L230 ◽

Cited By ~ 68

Author(s):

André Dagenais ◽

Christine Denis ◽

Marie-France Vives ◽

Sonia Girouard ◽

Chantal Massé ◽

...

Keyword(s):

Epithelial Cells ◽

Mrna Expression ◽

Time Course ◽

A549 Cells ◽

State Level ◽

Fold Increase ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial ◽

Atpase Gene ◽

The Impact

cAMP and dexamethasone are known to modulate Na+ transport in epithelial cells. We investigated whether dibutyryl cAMP (DBcAMP) and dexamethasone modulate the mRNA expression of two key elements of the Na+ transport system in isolated rat alveolar epithelial cells: α-, β-, and γ-subunits of the epithelial Na+channel (ENaC) and the α1- and β1-subunits of Na+-K+-ATPase. The cells were treated for up to 48 h with DBcAMP or dexamethasone to assess their long-term impact on the steady-state level of ENaC and Na+-K+-ATPase mRNA. DBcAMP induced a twofold transient increase of α-ENaC and α1-Na+-K+-ATPase mRNA that peaked after 8 h of treatment. It also upregulated β- and γ-ENaC mRNA but not β1-Na+-K+-ATPase mRNA. Dexamethasone augmented α-ENaC mRNA expression 4.4-fold in cells treated for 24 h and also upregulated β- and γ-ENaC mRNA. There was a 1.6-fold increase at 8 h of β1-Na+-K+-ATPase mRNA but no significant modulation of α1-Na+-K+-ATPase mRNA expression. Because DBcAMP and dexamethasone did not increase the stability of α-ENaC mRNA, we cloned 3.2 kb of the 5′ sequences flanking the mouse α-ENaC gene to study the impact of DBcAMP and dexamethasone on α-ENaC promoter activity. The promoter was able to drive basal expression of the chloramphenicol acetyltransferase (CAT) reporter gene in A549 cells. Dexamethasone increased the activity of the promoter by a factor of 5.9. To complete the study, the physiological effects of DBcAMP and dexamethasone were investigated by measuring transepithelial current in treated and control cells. DBcAMP and dexamethasone modulated transepithelial current with a time course reminiscent of the profile observed for α-ENaC mRNA expression. DBcAMP had a greater impact on transepithelial current (2.5-fold increase at 8 h) than dexamethasone (1.8-fold increase at 24 h). These results suggest that modulation of α-ENaC and Na+-K+-ATPase gene expression is one of the mechanisms that regulates Na+ transport in alveolar epithelial cells.

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Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

Respiratory Research ◽

10.1186/s12931-021-01646-7 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Zhenzhen Ma ◽

Chunyan Ma ◽

Qingfeng Zhang ◽

Yang Bai ◽

Kun Mu ◽

...

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Alveolar Type ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Tgf Β1

AbstractAlveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial–mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.

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Stretch induces cytokine release by alveolar epithelial cells in vitro

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.1.l167 ◽

1999 ◽

Vol 277 (1) ◽

pp. L167-L173 ◽

Cited By ~ 98

Author(s):

Nicholas E. Vlahakis ◽

Mark A. Schroeder ◽

Andrew H. Limper ◽

Rolf D. Hubmayr

Keyword(s):

Epithelial Cells ◽

Cell Damage ◽

A549 Cells ◽

Alveolar Epithelium ◽

Alveolar Epithelial Cells ◽

Structural Cell ◽

Alveolar Epithelial ◽

Macrophage Colony ◽

Factor Α

Mechanical ventilation can injure the lung, causing edema and alveolar inflammation. Interleukin-8 (IL-8) plays an important role in this inflammatory response. We postulated that cyclic cell stretch upregulates the production and release of IL-8 by human alveolar epithelium in the absence of structural cell damage or paracrine stimulation. To test this hypothesis, alveolar epithelial cells (A549 cells) were cultured on a deformable silicoelastic membrane. When stretched by 30% for up to 48 h, the cells released 49 ± 34% more IL-8 ( P < 0.001) than static controls. Smaller deformations (20% stretch) produced no consistent increase in IL-8. Stretch of 4 h duration increased IL-8 gene transcription fourfold above baseline. Stretch had no effect on cell proliferation, cell viability as assessed by51Cr release assay, or the release of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α. We conclude that deformation per se can trigger inflammatory signaling and that alveolar epithelial cells may be active participants in the alveolitis associated with ventilator-induced lung injury.

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Hispidin attenuates bleomycin-induced idiopathic pulmonary fibrosis via an anti-oxidative effect in A549 cells

Applied Biological Chemistry ◽

10.1186/s13765-021-00646-x ◽

2021 ◽

Vol 64 (1) ◽

Author(s):

Chen-Xi Ren ◽

Xin Jin ◽

Dan-Ping Xie ◽

Xiao-Yu Guo ◽

Li-Yun Yu ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Interstitial Fibrosis ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Oxidative Effects

AbstractIdiopathic pulmonary fibrosis (IPF) is a serious and irreversible chronic lung disease. Bleomycin (BLM) is an anticancer drug, which can cause severe lung toxicity. The main target of oxidative stress-induced lung injury is alveolar epithelial cells, which lead to interstitial fibrosis. The present study investigated whether hispidin (HP), which has excellent antioxidant activity, attenuates bleomycin-induced pulmonary fibrosis via anti-oxidative effects in A549 cells. We found that hispidin reduced bleomycin-induced fibrosis of A549 cells by reducing reactive oxygen species (ROS) levels and inhibiting epithelial-mesenchymal transition. Taken together, our data suggest that hispidin has therapeutic potential in preventing bleomycin-induced pulmonary fibrosis.

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Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

Mediators of Inflammation ◽

10.1155/2013/209179 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 27

Author(s):

Minrui Liang ◽

Jiucun Wang ◽

Haiyan Chu ◽

Xiaoxia Zhu ◽

Hang He ◽

...

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

Epithelial To Mesenchymal Transition ◽

Alveolar Epithelial Cell ◽

Smooth Muscle Actin ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Epithelial Cell Line ◽

Mesenchymal Transition ◽

Alveolar Epithelial

Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL-) 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM-) induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 producedγδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT) and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA)) and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

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