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PD-1 up-regulation on CD4 T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production.
Celada LJ, Kropski JA, Herazo-Maya JD, Luo W, Creecy A, Abad AT, Chioma OS, Lee G, Hassell NE, Shaginurova GI, Wang Y, Johnson JE, Kerrigan A, Mason WR, Baughman RP, Ayers GD, Bernard GR, Culver DA, Montgomery CG, Maher TM, Molyneaux PL, Noth I, Mutsaers SE, Prele CM, Peebles RS, Newcomb DC, Kaminski N, Blackwell TS, Van Kaer L, Drake WP
(2018) Sci Transl Med 10:
MeSH Terms: Adult, Aged, Animals, Bleomycin, CD4-Positive T-Lymphocytes, Cell Proliferation, Collagen Type I, Disease Models, Animal, Female, Fibroblasts, Gene Expression Regulation, Humans, Idiopathic Pulmonary Fibrosis, Interleukin-17, Male, Mice, Middle Aged, Programmed Cell Death 1 Receptor, RNA, Messenger, STAT3 Transcription Factor, Sarcoidosis, Th17 Cells, Transforming Growth Factor beta1, Up-Regulation
Show Abstract · Added March 26, 2019
Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1CD4 T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4 T cells. PD-1 T helper 17 cells are the predominant CD4 T cell subset expressing TGF-β. Coculture of PD-1CD4 T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4 T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1CD4 T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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24 MeSH Terms
Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome.
Young LR, Gulleman PM, Short CW, Tanjore H, Sherrill T, Qi A, McBride AP, Zaynagetdinov R, Benjamin JT, Lawson WE, Novitskiy SV, Blackwell TS
(2016) JCI Insight 1: e88947
MeSH Terms: Animals, Bleomycin, Chemokine CCL2, Disease Susceptibility, Epithelial Cells, Female, Hermanski-Pudlak Syndrome, Macrophages, Male, Mice, Mice, Inbred C57BL, Protein-Serine-Threonine Kinases, Pulmonary Alveoli, Pulmonary Fibrosis, Receptor, Transforming Growth Factor-beta Type II, Receptors, CCR2, Receptors, Transforming Growth Factor beta, Transforming Growth Factor beta
Show Abstract · Added March 29, 2017
Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic remodeling are incompletely understood. Since increased macrophage recruitment precedes pulmonary fibrosis in HPS, we investigated whether crosstalk between AECs and macrophages determines fibrotic susceptibility. We found that AECs from HPS mice produce excessive MCP-1, which was associated with increased macrophages in the lungs of unchallenged HPS mice. Blocking MCP-1/CCR2 signaling in HPS mice with genetic deficiency of CCR2 or targeted deletion of MCP-1 in AECs normalized macrophage recruitment, decreased AEC apoptosis, and reduced lung fibrosis in these mice following treatment with low-dose bleomycin. We observed increased TGF-β production by HPS macrophages, which was eliminated by CCR2 deletion. Selective deletion of TGF-β in myeloid cells or of TGF-β signaling in AECs through deletion of TGFBR2 protected HPS mice from AEC apoptosis and bleomycin-induced fibrosis. Together, these data reveal a feedback loop in which increased MCP-1 production by dysfunctional AECs results in recruitment and activation of lung macrophages that produce TGF-β, thus amplifying the fibrotic cascade through AEC apoptosis and stimulation of fibrotic remodeling.
1 Communities
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18 MeSH Terms
Bleomycin induced epithelial-mesenchymal transition (EMT) in pleural mesothelial cells.
Chen LJ, Ye H, Zhang Q, Li FZ, Song LJ, Yang J, Mu Q, Rao SS, Cai PC, Xiang F, Zhang JC, Su Y, Xin JB, Ma WL
(2015) Toxicol Appl Pharmacol 283: 75-82
MeSH Terms: Animals, Antibiotics, Antineoplastic, Bleomycin, Cell Line, Dose-Response Relationship, Drug, Epithelial-Mesenchymal Transition, Epithelium, Humans, Lung, Male, Mice, Mice, Inbred C57BL, Respiratory Mucosa
Show Abstract · Added January 20, 2015
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial-mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro, and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo. Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis.
Copyright © 2015. Published by Elsevier Inc.
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13 MeSH Terms
β-catenin in the alveolar epithelium protects from lung fibrosis after intratracheal bleomycin.
Tanjore H, Degryse AL, Crossno PF, Xu XC, McConaha ME, Jones BR, Polosukhin VV, Bryant AJ, Cheng DS, Newcomb DC, McMahon FB, Gleaves LA, Blackwell TS, Lawson WE
(2013) Am J Respir Crit Care Med 187: 630-9
MeSH Terms: Animals, Bleomycin, Disease Models, Animal, Epithelium, In Situ Nick-End Labeling, Lung Injury, Mice, Mice, Transgenic, Pulmonary Alveoli, Pulmonary Fibrosis, Wound Healing, beta Catenin
Show Abstract · Added March 5, 2014
RATIONALE - Alveolar epithelial cells (AECs) play central roles in the response to lung injury and the pathogenesis of pulmonary fibrosis.
OBJECTIVES - We aimed to determine the role of β-catenin in alveolar epithelium during bleomycin-induced lung fibrosis.
METHODS - Genetically modified mice were developed to selectively delete β-catenin in AECs and were crossed to cell fate reporter mice that express β-galactosidase (βgal) in cells of AEC lineage. Mice were given intratracheal bleomycin (0.04 units) and assessed for AEC death, inflammation, lung injury, and fibrotic remodeling. Mouse lung epithelial cells (MLE12) with small interfering RNA knockdown of β-catenin underwent evaluation for wound closure, proliferation, and bleomycin-induced cytotoxicity.
MEASUREMENTS AND MAIN RESULTS - Increased β-catenin expression was noted in lung parenchyma after bleomycin. Mice with selective deletion of β-catenin in AECs had greater AEC death at 1 week after bleomycin, followed by increased numbers of fibroblasts and enhanced lung fibrosis as determined by semiquantitative histological scoring and total collagen content. However, no differences in lung inflammation or protein levels in bronchoalveolar lavage were noted. In vitro, β-catenin-deficient AECs showed increased bleomycin-induced cytotoxicity as well as reduced proliferation and impaired wound closure. Consistent with these findings, mice with AEC β-catenin deficiency showed delayed recovery after bleomycin.
CONCLUSIONS - β-Catenin in the alveolar epithelium protects against bleomycin-induced fibrosis. Our studies suggest that AEC survival and wound healing are enhanced through β-catenin-dependent mechanisms. Activation of the developmentally important β-catenin pathway in AECs appears to contribute to epithelial repair after epithelial injury.
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12 MeSH Terms
The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky-Pudlak syndrome.
Young LR, Gulleman PM, Bridges JP, Weaver TE, Deutsch GH, Blackwell TS, McCormack FX
(2012) Am J Respir Crit Care Med 186: 1014-24
MeSH Terms: Adaptor Protein Complex 3, Animals, Bleomycin, Genetic Predisposition to Disease, Hermanski-Pudlak Syndrome, Humans, Lung, Macrophage Activation, Macrophages, Alveolar, Mice, Mice, Knockout, Mutation, Protein Transport, Pulmonary Alveoli, Pulmonary Fibrosis, Respiratory Mucosa
Show Abstract · Added March 5, 2014
RATIONALE - Hermansky-Pudlak syndrome (HPS) is a family of recessive disorders of intracellular trafficking defects that are associated with highly penetrant pulmonary fibrosis. Naturally occurring HPS mice reliably model important features of the human disease, including constitutive alveolar macrophage activation and susceptibility to profibrotic stimuli.
OBJECTIVES - To decipher which cell lineage(s) in the alveolar compartment is the predominant driver of fibrotic susceptibility in HPS.
METHODS - We used five different HPS and Chediak-Higashi mouse models to evaluate genotype-specific fibrotic susceptibility. To determine whether intrinsic defects in HPS alveolar macrophages cause fibrotic susceptibility, we generated bone marrow chimeras in HPS and wild-type mice. To directly test the contribution of the pulmonary epithelium, we developed a transgenic model with epithelial-specific correction of the HPS2 defect in an HPS mouse model.
MEASUREMENTS AND MAIN RESULTS - Bone marrow transplantation experiments demonstrated that both constitutive alveolar macrophage activation and increased susceptibility to bleomycin-induced fibrosis were conferred by the genotype of the lung epithelium, rather than that of the bone marrow-derived, cellular compartment. Furthermore, transgenic epithelial-specific correction of the HPS defect significantly attenuated bleomycin-induced alveolar epithelial apoptosis, fibrotic susceptibility, and macrophage activation. Type II cell apoptosis was genotype specific, caspase dependent, and correlated with the degree of fibrotic susceptibility.
CONCLUSIONS - We conclude that pulmonary fibrosis in naturally occurring HPS mice is driven by intracellular trafficking defects that lower the threshold for pulmonary epithelial apoptosis. Our findings demonstrate a pivotal role for the alveolar epithelium in the maintenance of alveolar homeostasis and regulation of alveolar macrophage activation.
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16 MeSH Terms
Intratracheal bleomycin causes airway remodeling and airflow obstruction in mice.
Polosukhin VV, Degryse AL, Newcomb DC, Jones BR, Ware LB, Lee JW, Loyd JE, Blackwell TS, Lawson WE
(2012) Exp Lung Res 38: 135-46
MeSH Terms: Airway Obstruction, Airway Remodeling, Animals, Antibiotics, Antineoplastic, Bleomycin, Disease Models, Animal, Epithelial Cells, Female, Fibroblasts, Humans, Idiopathic Pulmonary Fibrosis, Inflammation, Lung, Male, Mice, Mice, Inbred C57BL, S100 Calcium-Binding Protein A4, S100 Proteins, Transforming Growth Factor beta1, Transforming Growth Factor beta2
Show Abstract · Added March 5, 2014
In addition to parenchymal fibrosis, fibrotic remodeling of the distal airways has been reported in interstitial lung diseases. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary fibrosis (IPF) and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for fibrosis and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling) assay, and immunohistochemistry for transforming growth factor β1 (TGFβ1), TGFβ2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and fibrosis and greater airflow resistance after high-dose bleomycin. Increased TUNEL(+) bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFβ1 and TGFβ2 and accumulation of S100A4(+) fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. IPF is characterized by small airway remodeling in addition to parenchymal fibrosis, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial fibrosis. Thus, this model can be utilized to investigate mechanisms of airway remodeling.
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20 MeSH Terms
Telomerase deficiency does not alter bleomycin-induced fibrosis in mice.
Degryse AL, Xu XC, Newman JL, Mitchell DB, Tanjore H, Polosukhin VV, Jones BR, McMahon FB, Gleaves LA, Phillips JA, Cogan JD, Blackwell TS, Lawson WE
(2012) Exp Lung Res 38: 124-34
MeSH Terms: Airway Remodeling, Animals, Antibiotics, Antineoplastic, Bleomycin, Collagen, Epithelial Cells, Female, Idiopathic Pulmonary Fibrosis, Leukocytes, Lung, Male, Mice, Mice, Inbred C57BL, Mutation, Pneumonia, Pulmonary Alveoli, RNA, Telomerase, Telomere Homeostasis, Telomere Shortening
Show Abstract · Added March 5, 2014
Idiopathic pulmonary fibrosis (IPF) is characterized by interstitial lung infiltrates, dyspnea, and progressive respiratory failure. Reports linking telomerase mutations to familial interstitial pneumonia (FIP) suggest that telomerase activity and telomere length maintenance are important in disease pathogenesis. To investigate the role of telomerase in lung fibrotic remodeling, intratracheal bleomycin was administered to mice deficient in telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) and to wild-type controls. TERT-deficient and TERC-deficient mice were interbred to the F6 and F4 generation, respectively, when they developed skin manifestations and infertility. Fibrosis was scored using a semiquantitative scale and total lung collagen was measured using a hydroxyprolinemicroplate assay. Telomere lengths were measured in peripheral blood leukocytes and isolated type II alveolar epithelial cells (AECs). Telomerase activity in type II AECs was measured using a real-time polymerase chain reaction (PCR)-based system. Following bleomycin, TERT-deficient and TERC-deficient mice developed an equivalent inflammatory response and similar lung fibrosis (by scoring of lung sections and total lung collagen content) compared to controls, a pattern seen in both early (F1) and later (F6 TERT and F4 TERC) generations. Telomere lengths were reduced in peripheral blood leukocytes and isolated type II AECs from F6 TERT-deficient and F4 TERC-deficient mice compared to controls. Telomerase deficiency in a murine model leads to telomere shortening, but does not predispose to enhanced bleomycin-induced lung fibrosis. Additional genetic or environmental factors may be necessary for development of fibrosis in the presence of telomerase deficiency.
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20 MeSH Terms
Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis.
Tanjore H, Blackwell TS, Lawson WE
(2012) Am J Physiol Lung Cell Mol Physiol 302: L721-9
MeSH Terms: Aging, Animals, Apoptosis, Bleomycin, Endoplasmic Reticulum Stress, Epithelial-Mesenchymal Transition, Humans, Idiopathic Pulmonary Fibrosis, Inflammation, Mice, Pulmonary Alveoli, Pulmonary Surfactant-Associated Protein C, Smoking, Unfolded Protein Response
Show Abstract · Added March 5, 2014
While the factors that regulate the onset and progression of idiopathic pulmonary fibrosis (IPF) are incompletely understood, recent investigations have revealed that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are prominent in alveolar epithelial cells in this disease. Initial observations linking ER stress and IPF were made in cases of familial interstitial pneumonia (FIP), the familial form of IPF, in a family with a mutation in surfactant protein C (SFTPC). Subsequent studies involving lung biopsy specimens revealed that ER stress markers are highly expressed in the alveolar epithelium in IPF and FIP. Recent mouse modeling has revealed that induction of ER stress in the alveolar epithelium predisposed to enhanced lung fibrosis after treatment with bleomycin, which is mediated at least in part by increased alveolar epithelial cell (AEC) apoptosis. Emerging data also indicate that ER stress in AECs could impact fibrotic remodeling by altering inflammatory responses and inducing epithelial-mesenchymal transition. Although the cause of ER stress in IPF remains unknown, common environmental exposures such as herpesviruses, inhaled particulates, and cigarette smoke induce ER stress and are candidates for contributing to AEC dysfunction by this mechanism. Together, investigations to date suggest that ER stress predisposes to AEC dysfunction and subsequent lung fibrosis. However, many questions remain regarding the role of ER stress in initiation and progression of lung fibrosis, including whether ER stress or the UPR could be targeted for therapeutic benefit.
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14 MeSH Terms
PGI synthase overexpression protects against bleomycin-induced mortality and is associated with increased Nqo 1 expression.
Zhou W, Dowell DR, Geraci MW, Blackwell TS, Collins RD, Polosukhin VV, Lawson WE, Wu P, Sussan T, Biswal S, Goleniewska K, O'Neal J, Newcomb DC, Toki S, Morrow JD, Peebles RS
(2011) Am J Physiol Lung Cell Mol Physiol 301: L615-22
MeSH Terms: Acute Lung Injury, Animals, Apoptosis, Bleomycin, Bronchoalveolar Lavage Fluid, Epoprostenol, F2-Isoprostanes, Female, Gas Chromatography-Mass Spectrometry, Gene Expression, Humans, Immunohistochemistry, Lung, Mice, Mice, Transgenic, NAD(P)H Dehydrogenase (Quinone), Polymerase Chain Reaction, Prostaglandin-Endoperoxide Synthases, Reactive Oxygen Species, Receptors, Epoprostenol, Respiratory Function Tests, Respiratory Mucosa, Signal Transduction, Survival Rate
Show Abstract · Added March 5, 2014
The mortality rate for acute lung injury (ALI) is reported to be between 35-40%, and there are very few treatment strategies that improve the death rate from this condition. Previous studies have suggested that signaling through the prostaglandin (PG) I(2) receptor may protect against bleomycin-induced ALI in mice. We found that mice that overexpress PGI synthase (PGIS) in the airway epithelium were significantly protected against bleomycin-induced mortality and had reduced parenchymal consolidation, apoptosis of lung tissue, and generation of F(2)-isoprostanes compared with littermate wild-type controls. In addition, we show for the first time in both in vivo and in vitro experiments that PGI(2) induced the expression of NADP (H): quinoneoxidoreductase 1 (Nqo 1), an enzyme that prevents the generation of reactive oxygen species. PGI(2) induction of Nqo 1 provides a possible novel mechanism by which this prostanoid protects against bleomycin-induced mortality and identifies a potential therapeutic target for human ALI.
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24 MeSH Terms
Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs.
Lawson WE, Cheng DS, Degryse AL, Tanjore H, Polosukhin VV, Xu XC, Newcomb DC, Jones BR, Roldan J, Lane KB, Morrisey EE, Beers MF, Yull FE, Blackwell TS
(2011) Proc Natl Acad Sci U S A 108: 10562-7
MeSH Terms: Animals, Apoptosis, Bleomycin, Endoplasmic Reticulum, Intercellular Signaling Peptides and Proteins, Lung, Mice, Mice, Transgenic, Mutation, Peptides, Pulmonary Fibrosis, Reverse Transcriptase Polymerase Chain Reaction, Tunicamycin
Show Abstract · Added February 26, 2013
Evidence of endoplasmic reticulum (ER) stress has been found in lungs of patients with familial and sporadic idiopathic pulmonary fibrosis. We tested whether ER stress causes or exacerbates lung fibrosis by (i) conditional expression of a mutant form of surfactant protein C (L188Q SFTPC) found in familial interstitial pneumonia and (ii) intratracheal treatment with the protein misfolding agent tunicamycin. We developed transgenic mice expressing L188Q SFTPC exclusively in type II alveolar epithelium by using the Tet-On system. Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis was identified in the absence of a second profibrotic stimulus. After intratracheal bleomycin, L188Q SFTPC-expressing mice developed exaggerated lung fibrosis and reduced static lung compliance compared with controls. Bleomycin-treated L188Q SFTPC mice also demonstrated increased apoptosis of alveolar epithelial cells and greater numbers of fibroblasts in the lungs. With a complementary model, intratracheal tunicamycin treatment failed to induce lung remodeling yet resulted in augmentation of bleomycin-induced fibrosis. These data support the concept that ER stress produces a dysfunctional epithelial cell phenotype that facilitates fibrotic remodeling. ER stress pathways may serve as important therapeutic targets in idiopathic pulmonary fibrosis.
3 Communities
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13 MeSH Terms