免疫细胞在特发性肺纤维化发病机制中的作用研究进展
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摘要
特发性肺纤维化是极具破坏性,与年龄相关且病因不明的一种疾病,因此可选择的治疗方案十分有限。研究显示,固有免疫细胞和适应性免疫细胞在特发性肺纤维化发病过程中均发挥着十分重要的作用。在这里,我们总结并讨论了免疫细胞在特发性肺纤维化疾病中所扮演的角色,同时归纳了一些针对特发性肺纤维化的免疫治疗手段。
Idiopathic pulmonary fibrosis is a devastating,age-related lung disease of unknown cause that has few treatment options. Studies have shown that both innate and adaptive immune cells play an important role in the pathogenesis of idiopathic pulmonary fibrosis. Here,we summarize and discuss the role of immune cells involved in idiopathic pulmonary fibrosis,summing up some immunebased therapeutic strategies in the field.
Idiopathic pulmonary fibrosis is a devastating,age-related lung disease of unknown cause that has few treatment options. Studies have shown that both innate and adaptive immune cells play an important role in the pathogenesis of idiopathic pulmonary fibrosis. Here,we summarize and discuss the role of immune cells involved in idiopathic pulmonary fibrosis,summing up some immunebased therapeutic strategies in the field.
引文
[1] Collard HR,Chen SY,Yeh WS,et al. Health care utilization and costs of idiopathic pulmonary fibrosis in U. S. Medicare beneficiaries aged 65 years and older[J]. Ann Am Thorac Soc,2015,7(12):981-987.
[2] King TE,Pardo A,Selman M. Idiopathic pulmonary fibrosis[J].Lancet,2011,9807(378):1949-1961.
[3] Wynn TA. Integrating mechanisms of pulmonary fibrosis[J]. J Exp Med,2011,7(208):1339-1350.
[4] Richeldi L,Collard HR,Jones MG. Idiopathic pulmonary fibrosis[J]. Lancet,2017,10082(389):1941-1952.
[5] Mora AL,Rojas M,Pardo A,et al. Emerging therapies for idiopathic pulmonary fibrosis,a progressive age-related disease[J].Nat Rev Drug Discov,2017,11(16):755-772.
[6] Larson-Casey JL,Deshane JS,Ryan AJ,et al. Macrophage Akt1kinase-mediated mitophagy modulates apoptosis resistance and pulmonary fibrosis[J]. Immunity,2016,3(44):582-596.
[7] Byrne AJ,Mathie SA,Gregory LG,et al. Pulmonary macrophages:key players in the innate defence of the airways[J]. Thorax,2015,12(70):1189-1196.
[8] Murray PJ,Wynn TA. Protective and pathogenic functions of macrophage subsets[J]. Nat Rev Immunol,2011,11(11):723-737.
[9] Craig VJ,Zhang L,Hagood JS,et al. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis[J]. Am J Respir Cell Mol Biol,2015,5(53):585-600.
[10] Huen SC,Moeckel GW,Cantley LG. Macrophage-specific deletion of transforming growth factor-beta1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury[J]. Am J Physiol Renal Physiol,2013,4(305):F477-F484.
[11] Barron L,Wynn TA. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages[J]. Am J Physiol Gastrointest Liver Physiol,2011,5(300):G723-728.
[12] Ji WJ,Ma YQ,Zhou X,et al. Temporal and spatial characterization of mononuclear phagocytes in circulating,lung alveolar and interstitial compartments in a mouse model of bleomycininduced pulmonary injury[J]. J Immunol Methods,2014,1-2(403):7-16.
[13] Kruger P,Saffarzadeh M,Weber AN,et al. Neutrophils:Between host defence,immune modulation,and tissue injury[J]. PLo S Pathog,2015,3(11):e1004651.
[14] Puerta-Arias JD,Pino-Tamayo PA,Arango JC,et al. Depletion of neutrophils promotes the resolution of pulmonary inflammation and fibrosis in mice infected with paracoccidioides brasiliensis[J]. PLo S One,2016,9(11):e0163985.
[15] Kinder BW,Brown KK,Schwarz MI,et al. Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis[J]. Chest,2008,1(133):226-232.
[16] Ashitani J,Mukae H,Taniguchi H,et al. Granulocyte-colony stimulating factor levels in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis[J]. Thorax,1999,11(54):1015-1020.
[17] Inage M,Nakamura H,Kato S,et al. Levels of cytokeratin 19fragments in bronchoalveolar lavage fluid correlate to the intensity of neutrophil and eosinophil-alveolitis in patients with idiopathic pulmonary fibrosis[J]. Respir Med,2000,2(94):155-160.
[18] Obayashi Y,Yamadori I,Fujita J,et al. The role of neutrophils in the pathogenesis of idiopathic pulmonary fibrosis[J]. Chest,1997,5(112):1338-1343.
[19] Chua F,Dunsmore SE,Clingen PH,et al. Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis[J]. Am J Pathol,2007,1(170):65-74.
[20] Gregory AD,Kliment CR,Metz HE,et al. Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis[J]. J Leukoc Biol,2015,2(98):143-152.
[21] Takemasa A,Ishii Y,Fukuda T. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice[J]. Eur Respir J,2012,6(40):1475-1482.
[22] Fujimoto K,Kubo K,Yamaguchi S,et al. Eosinophil activation in patients with pulmonary fibrosis[J]. Chest,1995,1(108):48-54.
[23] Shen ZJ,Esnault S,Rosenthal LA,et al. Pin1 regulates TGF-beta1production by activated human and murine eosinophils and contributes to allergic lung fibrosis[J]. J Clin Invest,2008,2(118):479-490.
[24] Zhang K,Gharaee-Kermani M,Mc Garry B,et al. TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis[J]. J Immunol,1997,2(158):954-959.
[25] Hao H,Cohen DA,Jennings CD,et al. Bleomycin-induced pulmonary fibrosis is independent of eosinophils[J]. J Leukoc Biol,2000,4(68):515-521.
[25] Cha SI,Chang CS,Kim EK,et al. Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis[J].Histopathology,2012,1(61):98-106.
[27] Lindstedt KA,Wang Y,Shiota N,et al. Activation of paracrine TGF-beta1 signaling upon stimulation and degranulation of rat serosal mast cells:a novel function for chymase[J]. Faseb J,2001,8(15):1377-1388.
[28] Veerappan A,O'Connor NJ,Brazin J,et al. Mast cells:a pivotal role in pulmonary fibrosis[J]. DNA Cell Biol,2013,4(32):206-218.
[29] Wygrecka M,Dahal BK,Kosanovic D,et al. Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis:role of transmembrane SCF and the PAR-2/PKC-alpha/Raf-1/p44/42signaling pathway[J]. Am J Pathol,2013,6(182):2094-2108.
[30] Moiseeva EP,Roach KM,Leyland ML,et al. CADM1 is a key receptor mediating human mast cell adhesion to human lung fibroblasts and airway smooth muscle cells[J]. PLo S One,2013,4(8):e61579.
[31] Luzina IG,Todd NW,Iacono AT,et al. Roles of T lymphocytes in pulmonary fibrosis[J]. J Leukoc Biol,2008,2(83):237-244.
[32] Kimura T,Ishii Y,Yoh K,et al. Overexpression of the transcription factor GATA-3 enhances the development of pulmonary fibrosis[J]. Am J Pathol,2006,1(169):96-104.
[33] Parker JM,Glaspole IN,Lancaster LH,et al. A phase 2randomized controlled study of tralokinumab in subjects with idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med,2018,1(197):94-103.
[34] Desai O,Winkler J,Minasyan M,et al. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis[J]. Front Med(Lausanne),2018:5:43.
[35] Chen Y,Li C,Weng D,et al. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice[J]. Toxicol Appl Pharmacol,2014,1(275):62-72.
[36] Lo Re S,Dumoutier L,Couillin I,et al. IL-17A-producing gammadelta T and Th17 lymphocytes mediate lung inflammation but not fibrosis in experimental silicosis[J]. J Immunol,2010,11(184):6367-6377.
[37] van den Brule S,Heymans J,Havaux X,et al. Profibrotic effect of IL-9 overexpression in a model of airway remodeling[J]. Am J Respir Cell Mol Biol,2007,2(37):202-209.
[38] Arras M,Louahed J,Heilier JF,et al. IL-9 protects against bleomycin-induced lung injury:involvement of prostaglandins[J]. Am J Pathol,2005,1(166):107-115.
[39] Galati D,De Martino M,Trotta A,et al. Peripheral depletion of NK cells and imbalance of the Treg/Th17 axis in idiopathic pulmonary fibrosis patients[J]. Cytokine,2014,2(66):119-126.
[40] Boveda-Ruiz D,D'Alessandro-Gabazza CN,Toda M,et al.Differential role of regulatory T cells in early and late stages of pulmonary fibrosis[J]. Immunobiology,2013,2(218):245-254.
[41] Xiong S,Guo R,Yang Z,et al. Treg depletion attenuates irradiation-induced pulmonary fibrosis by reducing fibrocyte accumulation,inducing Th17 response,and shifting IFN-gamma,IL-12/IL-4,IL-5 balance[J]. Immunobiology,2015,11(220):1284-1291.
[42] Kotsianidis I,Nakou E,Bouchliou I,et al. Global impairment of CD4+CD25+FOXP3+regulatory T cells in idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med,2009,12(179):1121-1130.
[43] Garibaldi BT,D'Alessio FR,Mock JR,et al. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment[J]. Am J Respir Cell Mol Biol,2013,1(48):35-43.
[44] Xue J,Kass DJ,Bon J,et al. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients[J]. J Immunol,2013,5(191):2089-2095.
[45] Todd NW,Scheraga RG,Galvin JR,et al. Lymphocyte aggregates persist and accumulate in the lungs of patients with idiopathic pulmonary fibrosis[J]. J Inflamm Res,2013,6:63-70.
[46] Francois A,Gombault A,Villeret B,et al. B cell activating factor is central to bleomycin-and IL-17-mediated experimental pulmonary fibrosis[J]. J Autoimmun,2015,56:1-11.
[47] Arras M,Louahed J,Simoen V,et al. B lymphocytes are critical for lung fibrosis control and prostaglandin E2 regulation in IL-9transgenic mice[J]. Am J Respir Cell Mol Biol,2006,5(34):573-580.
[48] Lee JS,Kim EJ,Lynch KL,et al. Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis[J]. Respir Med,2013,2(107):249-255.
[49] Li FJ,Surolia R,Li H,et al. Autoimmunity to vimentin is associated with outcomes of patients with idiopathic pulmonary fibrosis[J]. J Immunol,2017,5(199):1596-1605.
[50] Kahloon RA,Xue J,Bhargava A,et al. Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses[J]. Am J Respir Crit Care Med,2013,7(187):768-775.
[51] Wang C,Song X,Li Y,et al. Low-dose paclitaxel ameliorates pulmonary fibrosis by suppressing TGF-beta1/Smad3 pathway via miR-140 upregulation[J]. PLo S One,2013,8(8):e70725.
[52] Bouros D. Pirfenidore for idiopathic pulmonary fibrosis[J].Lancet,2011,9779(377):1727-1729.
[53] Giri SN,Hyde DM,Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice[J]. Thorax,1993,10(48):959-966.
[54] Milam JE,Keshamouni VG,Phan SH,et al. PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis[J]. Am J Physiol Lung Cell Mol Physiol,2008,5(294):L891-L901.
[55] Koh RY,Lim CL,Uhal BD,et al. Inhibition of transforming growth factor-beta via the activin receptor-like kinase-5 inhibitor attenuates pulmonary fibrosis[J]. Mol Med Rep,2015,5(11):3808-3813.
[56] Kolahian S,Fernandez IE,Eickelberg O,et al. Immune mechanisms in pulmonary fibrosis[J]. Am J Respir Cell Mol Biol,2016,3(55):309-322.
[57] Wilson MS,Madala SK,Ramalingam TR,et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent[J]. J Exp Med,2010,3(207):535-552.
[2] King TE,Pardo A,Selman M. Idiopathic pulmonary fibrosis[J].Lancet,2011,9807(378):1949-1961.
[3] Wynn TA. Integrating mechanisms of pulmonary fibrosis[J]. J Exp Med,2011,7(208):1339-1350.
[4] Richeldi L,Collard HR,Jones MG. Idiopathic pulmonary fibrosis[J]. Lancet,2017,10082(389):1941-1952.
[5] Mora AL,Rojas M,Pardo A,et al. Emerging therapies for idiopathic pulmonary fibrosis,a progressive age-related disease[J].Nat Rev Drug Discov,2017,11(16):755-772.
[6] Larson-Casey JL,Deshane JS,Ryan AJ,et al. Macrophage Akt1kinase-mediated mitophagy modulates apoptosis resistance and pulmonary fibrosis[J]. Immunity,2016,3(44):582-596.
[7] Byrne AJ,Mathie SA,Gregory LG,et al. Pulmonary macrophages:key players in the innate defence of the airways[J]. Thorax,2015,12(70):1189-1196.
[8] Murray PJ,Wynn TA. Protective and pathogenic functions of macrophage subsets[J]. Nat Rev Immunol,2011,11(11):723-737.
[9] Craig VJ,Zhang L,Hagood JS,et al. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis[J]. Am J Respir Cell Mol Biol,2015,5(53):585-600.
[10] Huen SC,Moeckel GW,Cantley LG. Macrophage-specific deletion of transforming growth factor-beta1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury[J]. Am J Physiol Renal Physiol,2013,4(305):F477-F484.
[11] Barron L,Wynn TA. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages[J]. Am J Physiol Gastrointest Liver Physiol,2011,5(300):G723-728.
[12] Ji WJ,Ma YQ,Zhou X,et al. Temporal and spatial characterization of mononuclear phagocytes in circulating,lung alveolar and interstitial compartments in a mouse model of bleomycininduced pulmonary injury[J]. J Immunol Methods,2014,1-2(403):7-16.
[13] Kruger P,Saffarzadeh M,Weber AN,et al. Neutrophils:Between host defence,immune modulation,and tissue injury[J]. PLo S Pathog,2015,3(11):e1004651.
[14] Puerta-Arias JD,Pino-Tamayo PA,Arango JC,et al. Depletion of neutrophils promotes the resolution of pulmonary inflammation and fibrosis in mice infected with paracoccidioides brasiliensis[J]. PLo S One,2016,9(11):e0163985.
[15] Kinder BW,Brown KK,Schwarz MI,et al. Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis[J]. Chest,2008,1(133):226-232.
[16] Ashitani J,Mukae H,Taniguchi H,et al. Granulocyte-colony stimulating factor levels in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis[J]. Thorax,1999,11(54):1015-1020.
[17] Inage M,Nakamura H,Kato S,et al. Levels of cytokeratin 19fragments in bronchoalveolar lavage fluid correlate to the intensity of neutrophil and eosinophil-alveolitis in patients with idiopathic pulmonary fibrosis[J]. Respir Med,2000,2(94):155-160.
[18] Obayashi Y,Yamadori I,Fujita J,et al. The role of neutrophils in the pathogenesis of idiopathic pulmonary fibrosis[J]. Chest,1997,5(112):1338-1343.
[19] Chua F,Dunsmore SE,Clingen PH,et al. Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis[J]. Am J Pathol,2007,1(170):65-74.
[20] Gregory AD,Kliment CR,Metz HE,et al. Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis[J]. J Leukoc Biol,2015,2(98):143-152.
[21] Takemasa A,Ishii Y,Fukuda T. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice[J]. Eur Respir J,2012,6(40):1475-1482.
[22] Fujimoto K,Kubo K,Yamaguchi S,et al. Eosinophil activation in patients with pulmonary fibrosis[J]. Chest,1995,1(108):48-54.
[23] Shen ZJ,Esnault S,Rosenthal LA,et al. Pin1 regulates TGF-beta1production by activated human and murine eosinophils and contributes to allergic lung fibrosis[J]. J Clin Invest,2008,2(118):479-490.
[24] Zhang K,Gharaee-Kermani M,Mc Garry B,et al. TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis[J]. J Immunol,1997,2(158):954-959.
[25] Hao H,Cohen DA,Jennings CD,et al. Bleomycin-induced pulmonary fibrosis is independent of eosinophils[J]. J Leukoc Biol,2000,4(68):515-521.
[25] Cha SI,Chang CS,Kim EK,et al. Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis[J].Histopathology,2012,1(61):98-106.
[27] Lindstedt KA,Wang Y,Shiota N,et al. Activation of paracrine TGF-beta1 signaling upon stimulation and degranulation of rat serosal mast cells:a novel function for chymase[J]. Faseb J,2001,8(15):1377-1388.
[28] Veerappan A,O'Connor NJ,Brazin J,et al. Mast cells:a pivotal role in pulmonary fibrosis[J]. DNA Cell Biol,2013,4(32):206-218.
[29] Wygrecka M,Dahal BK,Kosanovic D,et al. Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis:role of transmembrane SCF and the PAR-2/PKC-alpha/Raf-1/p44/42signaling pathway[J]. Am J Pathol,2013,6(182):2094-2108.
[30] Moiseeva EP,Roach KM,Leyland ML,et al. CADM1 is a key receptor mediating human mast cell adhesion to human lung fibroblasts and airway smooth muscle cells[J]. PLo S One,2013,4(8):e61579.
[31] Luzina IG,Todd NW,Iacono AT,et al. Roles of T lymphocytes in pulmonary fibrosis[J]. J Leukoc Biol,2008,2(83):237-244.
[32] Kimura T,Ishii Y,Yoh K,et al. Overexpression of the transcription factor GATA-3 enhances the development of pulmonary fibrosis[J]. Am J Pathol,2006,1(169):96-104.
[33] Parker JM,Glaspole IN,Lancaster LH,et al. A phase 2randomized controlled study of tralokinumab in subjects with idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med,2018,1(197):94-103.
[34] Desai O,Winkler J,Minasyan M,et al. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis[J]. Front Med(Lausanne),2018:5:43.
[35] Chen Y,Li C,Weng D,et al. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice[J]. Toxicol Appl Pharmacol,2014,1(275):62-72.
[36] Lo Re S,Dumoutier L,Couillin I,et al. IL-17A-producing gammadelta T and Th17 lymphocytes mediate lung inflammation but not fibrosis in experimental silicosis[J]. J Immunol,2010,11(184):6367-6377.
[37] van den Brule S,Heymans J,Havaux X,et al. Profibrotic effect of IL-9 overexpression in a model of airway remodeling[J]. Am J Respir Cell Mol Biol,2007,2(37):202-209.
[38] Arras M,Louahed J,Heilier JF,et al. IL-9 protects against bleomycin-induced lung injury:involvement of prostaglandins[J]. Am J Pathol,2005,1(166):107-115.
[39] Galati D,De Martino M,Trotta A,et al. Peripheral depletion of NK cells and imbalance of the Treg/Th17 axis in idiopathic pulmonary fibrosis patients[J]. Cytokine,2014,2(66):119-126.
[40] Boveda-Ruiz D,D'Alessandro-Gabazza CN,Toda M,et al.Differential role of regulatory T cells in early and late stages of pulmonary fibrosis[J]. Immunobiology,2013,2(218):245-254.
[41] Xiong S,Guo R,Yang Z,et al. Treg depletion attenuates irradiation-induced pulmonary fibrosis by reducing fibrocyte accumulation,inducing Th17 response,and shifting IFN-gamma,IL-12/IL-4,IL-5 balance[J]. Immunobiology,2015,11(220):1284-1291.
[42] Kotsianidis I,Nakou E,Bouchliou I,et al. Global impairment of CD4+CD25+FOXP3+regulatory T cells in idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med,2009,12(179):1121-1130.
[43] Garibaldi BT,D'Alessio FR,Mock JR,et al. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment[J]. Am J Respir Cell Mol Biol,2013,1(48):35-43.
[44] Xue J,Kass DJ,Bon J,et al. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients[J]. J Immunol,2013,5(191):2089-2095.
[45] Todd NW,Scheraga RG,Galvin JR,et al. Lymphocyte aggregates persist and accumulate in the lungs of patients with idiopathic pulmonary fibrosis[J]. J Inflamm Res,2013,6:63-70.
[46] Francois A,Gombault A,Villeret B,et al. B cell activating factor is central to bleomycin-and IL-17-mediated experimental pulmonary fibrosis[J]. J Autoimmun,2015,56:1-11.
[47] Arras M,Louahed J,Simoen V,et al. B lymphocytes are critical for lung fibrosis control and prostaglandin E2 regulation in IL-9transgenic mice[J]. Am J Respir Cell Mol Biol,2006,5(34):573-580.
[48] Lee JS,Kim EJ,Lynch KL,et al. Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis[J]. Respir Med,2013,2(107):249-255.
[49] Li FJ,Surolia R,Li H,et al. Autoimmunity to vimentin is associated with outcomes of patients with idiopathic pulmonary fibrosis[J]. J Immunol,2017,5(199):1596-1605.
[50] Kahloon RA,Xue J,Bhargava A,et al. Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses[J]. Am J Respir Crit Care Med,2013,7(187):768-775.
[51] Wang C,Song X,Li Y,et al. Low-dose paclitaxel ameliorates pulmonary fibrosis by suppressing TGF-beta1/Smad3 pathway via miR-140 upregulation[J]. PLo S One,2013,8(8):e70725.
[52] Bouros D. Pirfenidore for idiopathic pulmonary fibrosis[J].Lancet,2011,9779(377):1727-1729.
[53] Giri SN,Hyde DM,Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice[J]. Thorax,1993,10(48):959-966.
[54] Milam JE,Keshamouni VG,Phan SH,et al. PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis[J]. Am J Physiol Lung Cell Mol Physiol,2008,5(294):L891-L901.
[55] Koh RY,Lim CL,Uhal BD,et al. Inhibition of transforming growth factor-beta via the activin receptor-like kinase-5 inhibitor attenuates pulmonary fibrosis[J]. Mol Med Rep,2015,5(11):3808-3813.
[56] Kolahian S,Fernandez IE,Eickelberg O,et al. Immune mechanisms in pulmonary fibrosis[J]. Am J Respir Cell Mol Biol,2016,3(55):309-322.
[57] Wilson MS,Madala SK,Ramalingam TR,et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent[J]. J Exp Med,2010,3(207):535-552.