丙戊酸钠减轻博莱霉素致大鼠肺纤维化

目的:探讨丙戊酸钠在博莱霉素诱导的肺纤维化中的作用及机制。方法:42只大鼠随机分为正常对照组、模型组和治疗组。造模采用博来霉素5 mg/kg气管内注射,自造模14 d开始分别采用生理盐水(0.5m L/d)、丙戊酸钠(300 mg·kg-1·d-1)和地塞米松(0.6 mg·kg-1·d-1)腹腔内注射治疗14 d。模型组分别在造模后14和、28 d处死。治疗组在造模后28 d处死。然后通过HE染色、Masson染色、羟脯氨酸(HYP)检测和Western blotting检测α-平滑肌肌动蛋白(α-SMA)及E-钙黏蛋白(E-cadherin)表达的变化,综合分析丙戊酸钠对肺纤维化发展的干预作用。结果:HE染色显示丙戊酸钠治疗组的肺泡结构、肺间质的形态优于生理盐水组和地塞米松治疗组。Masson染色及HYP检测用于衡量肺组织内胶原的分布及含量,可见丙戊酸钠治疗组肺组织内胶原的分布及含量均显著低于地塞米松治疗组及生理盐水组。丙戊酸钠可以降低α-SMA的表达,同时上调上皮标志性蛋白E-cadherin的表达。结论:丙戊酸钠可以通过减少胶原的表达与分布及下调间充质蛋白α-SMA,同时上调上皮蛋白E-cadherin的表达从而减轻博来霉素诱导大鼠肺纤维化。     

内皮素的表达与鼠肺纤维化的关系

目的：动态观察肺纤维化大鼠的内皮素合成和分布,了解ET与肺纤维化发生发展的关系。方法：采用放射免疫法和SP免疫组织化学方法,观察博莱霉素（BW）组（n＝25）和对照组（n＝25）在用药后1、3、7、14、28d时血浆EF浓度及肺组织财的合成和分布情况。结果.BLM组大鼠血浆ET含量明显高于正常对照组（P＜0．01）,ET在支气管上皮细胞和炎性细胞表达增强P＜0．01。结论：ET可能与肺纤维化的发生发展有密切关系,参与了肺纤维化的渗出和增生过程。     

三氧化二砷对博莱霉素致大鼠肺纤维化的影响及其作用机制

目的:观察三氧化二砷对博莱霉素致大鼠肺纤维化的影响及可能的作用机制。方法:SD大鼠气管内滴注博莱霉素诱导肺纤维化,腹腔内分别注射三氧化二砷(治疗组)、地塞米松(激素组)、生理盐水(模型组)进行干预。各组动物再按造模后开始干预的时间不同分为14d和28d开始干预2个亚组,每个亚组再按观察时间不同分为14d、28d和56d3个观察组。观察大鼠中位生存时间、肺组织羟脯氨酸含量、肺泡炎和肺纤维化程度(HE染色)、肺组织胶原定量分析(Masson染色)等指标来评价药物干预效果,并采用脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(TUNEL法)检测肺组织凋亡指数。同时对肺组织转化生长因子-β1(TGF-β1)、干扰素-γ(IFN-γ)、基质金属蛋白酶-9(MMP-9)、金属蛋白酶组织抑制物-1(TIMP-1)免疫组化染色结果进行定量分析。结果:(1)生存时间观察:造模后14d开始干预的模型组、治疗组和激素组的中位生存时间分别为30d、57d和19d(P0.01);而造模后28d开始干预的各组的中位生存时间为40d、58d和34d(P0.05)。(2)肺纤维化的比较:各治疗组大鼠的羟脯氨酸含量与模型组相比均有下降趋势。各治疗组的肺泡炎和肺纤维化程度均轻于模型组。与模型组相比,各治疗组的胶原面积均小于模型组。(3)肺组织凋亡指数的比较:与模型组相比,14d开始干预并观察14d、28d组和28d开始干预并观察14d组的治疗组大鼠凋亡指数明显升高。(4)14d开始干预的各组的细胞因子比较:各治疗组的肺组织中转化生长因子-β1(TGF-β1)免疫组化染色的平均光密度均低于相应模型组。治疗组中观察28d和56d小组的肺组织中干扰素-γ(IFN-γ)免疫组化染色的平均光密度均高于模型组。各治疗组的肺组织中基质金属蛋白酶-9(MMP-9)免疫组化染色平均光密度与模型组区别不明显。与模型组比较,各治疗组的肺组织中金属蛋白酶组织抑制物-1(TIMP-1)免疫组化染色平均光密度明显降低。结论:三氧化二砷能够减轻博莱霉素诱导的大鼠肺纤维化,其机制可能与诱导肺组织细胞凋亡增加有关。     

大鼠肺纤维化形成过程中肺内一氧化氮代谢的动态变化

目的:观察大鼠肺纤维化过程中肺内一氧化氮代谢的动态变化及其与肺纤维化形成的关系。方法:气管内一次性滴注平阳霉素(5mL/kg),观察注后7、14、21、30d和70d组大鼠肺组织羟脯氨酸含量,出、入肺血NO₂^-/NO₃^-含量以及14d组肺泡巨噬细胞培养上清液中NO₂^-/NO₃^-含量和肺间质诱导型一氧化氮合酶(iNOS)免疫组化阳性细胞数量的变化。结果:7d组大鼠肺组织羟脯氨酸含量与对照组比无明显差异,14d组高于对照组(P＜0.05),21d组、30d组和70d组更为明显(均P＜0.01)。7d组、14d组出肺血NO₂^-/NO₃^-含量明显高于对照组(均P＜0.01),入肺血NO₂^-/NO₃^-含量明显低于对照组(均P＜0.01),21d组出肺血NO₂^-/NO₃^-含量的变化无明显差异(P＞0.05),入肺血仍较低(P＜0.01),30d组和70d组出、入肺血NO₂^-/NO₃^-含量与对照组无明显差异(P＞0.05)。14d组大鼠肺泡巨噬细胞培养上清液中NO₂^-/NO₃^-含量明显高于对照组(P＜0.01)。14d组大鼠肺间质iNOS免疫组化阳性细胞增多。结论:大鼠肺纤维化形成过程中,先有肺内NO生成增多,后出现肺纤维化;在肺纤维化形成后,肺内NO趋向恢复。肺内NO增多与肺泡巨噬细胞释放NO能力增加、肺内iNOS的增多有关。肺内NO的大量生成可能是促使肺纤维化形成的因素之一。     

大鼠肺纤维化形成中肺巨噬细胞增殖和凋亡的变化

目的:观察肺纤维化形成过程中,肺泡巨噬细胞数量、增殖和凋亡的变化。方法:气管内滴注平阳霉素(BLMA₅)(5mg/kg),观察注后14d和30d组大鼠支气管肺泡灌洗液(BALF)中肺泡巨噬细胞数量、增殖和凋亡的变化以及细胞的MTT活力。结果:(1)BLMA₅14d组和30d组大鼠BALF中巨噬细胞数分别多于sham14d和30d组,(分别P＜0.01,P＜0.05);但BLMA₅30d组的细胞数明显少于BLMA₅14d组(P＜0.05);(2)BLMA₅14d组巨噬细胞增殖指数高于sham14d组(P＜0.05),而BLMA₅30d组增殖指数低于sham30d组(P＜0.05);(3)BLMA₅14d和30d组凋亡细胞数分别多于sham14d和30d组(均P＜0.01),但BLMA₅14d组少于BLMA₅30d组(P＜0.05);(4)BLMA₅14d和30d组大鼠BALF中巨噬细胞数MTT活力分别高于sham14d和30d组,分别P＜0.01,P＜0.05。结论:在肺纤维化形成过程中,肺巨噬细胞增殖能力先增强后减弱;而肺巨噬细胞凋亡始终增加,上述变化是导致肺巨噬细胞数量和功能变化的因素之一。     

Bone marrow mesenchymal stem cells protect against bleomycin-induced pulmonary fibrosis in rat by activating Nrf2 signaling

Pulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms of pulmonary fibrosis are not fully understood, oxidant/antioxidant may play an important role in many of the processes of inflammation and fibrosis. Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress. Mesenchymal stem cells (MSC) are in clinical trials for widespread indications including musculoskeletal, neurological, cardiac and haematological disorders. One emerging concept is that MSCs may have paracrine, rather than a functional, roles in lung injury repair and regeneration. In the present study, we investigated bone marrow mesenchymal stem cells (BMSCs) for the treatment of bleomycin-induced pulmonary fibrosis. Our results showed that BMSCs administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level. The gene expression levels of NAD(P)H: quinine oxidoreductase 1 (NQO1), gama-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2), attenuated by bleomycin, were increased up to basal levels after BMSCs transplantation. BMSCs significantly increased superoxide dismutase (SOD) activity and inhibited malondialdehyde (MDA) production in the injured lung. The present study provides evidence that BMSCs may be a potential therapeutic reagent for the treatment of lung fibrosis.     

Fine-tuning the ubiquitin-proteasome system to treat pulmonary fibrosis

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an extremely aggressive lung disease that develops almost exclusively in older individuals, carries a very poor prognosis, and lacks any truly effective therapies. The current conceptual model is that IPF develops because of an age-related decline in the ability of the lung epithelium to regenerate after injury, largely due to death or senescence of epithelial progenitor cells in the distal airways. This loss of regenerative capacity is thought to initiate a chronic and ineffective wound-healing response, characterized by persistent, low-grade lung inflammation and sustained production of collagen and other extracellular matrix materials. Despite recent advances in our understanding of IPF pathobiology, there remains a pressing need to further delineate underlying mechanisms to develop more effective therapies for this disease. In this review, we build the case that many of the manifestations of IPF result from a failure of cells to effectively manage their proteome. We propose that epithelial progenitor cells, as well as immune cells and fibroblasts, become functionally impaired, at least in part, because of an accumulation or a loss in the expression of various crucial proteins. Further, we propose that central to this defect is the dysregulation of the ubiquitin-proteasome system (UPS), which is the major protein-degradation system in eukaryotic cells. Lastly, borrowing concepts from other fields, we discuss how targeting the UPS system could be employed as a novel treatment for IPF and perhaps for other fibrotic lung diseases as well.     

Interstitial associations of cells lining air spaces in human pulmonary fibrosis

Summary An ultrastructural study of the cells that line air spaces in human pulmonary fibrosis is reported. Intimate associations between these cells and cellular elements in the interstitium were consistently found in biopsies from 25 cases. Cytoplasmic extensions of cuboidal pneumocytes protruded through discontinuities in the subjacent basement membrane. Attenuated cells having structural properties of fibroblasts were situated on connective tissue that formed the walls of numerous air spaces. In this situation, a basement membrane was not demonstrable. These heretofore undescribed features suggest a dynamic interaction between certain mesenchymal and epithelial elements in the fibrotic lung.This study is from a Specialized Center of Research (SCOR) in pulmonary disease supported by U.S. Public Health Service Grant No. HL-14212, from the National Heart and Lung Institute     

Ultrastructural study on human lung in alveolitis versus pulmonary fibrosis

Summary Lung specimens of 21 patients with diffuse interstitial lung disease were examined. The present ultrastructural study outlines the topography and distribution of inflammatory changes in the interstitium, endothelium, and in pneumocytes and phagocytes. Alveolitis is characterized by marked regenerative activity of type II pneumocytes (cuboid metaplasia), intraluminal macrophage accumulation, endothelial swelling, multilamination of the endothelial basement membrane, pericapillary edema, and primarily by cellular infiltrates in the interstitial space. The most prominent feature of the interstitium in pulmonary fibrosis is the lack of immunoinflammatory cells. In some areas there is a marked absence of alveolar lumen while only a small number of macrophages are present in the remaining alveolar lumen. Most of the capillaries in the fibrous septum have been destroyed. Ultrastructural studies of lung biopsies in patients with diffuse interstitial lung disease allow the differentiation between alveolitis and pulmonary fibrosis and thus contribute to a therapeutic decision.     

盐皮质激素受体在博来霉素诱导的实验性肺纤维化中的作用*

 目的：研究盐皮质激素受体（MR）在博来霉素诱导的实验性肺纤维化进展过程中的作用及机制。方法：将126只6～8周龄雄性C57BL/6小鼠随机分为对照组、博来霉素组和MR阻断剂螺内酯干预组,气管内一次性滴注博来霉素(2.5 mg/kg)溶液建立实验性小鼠肺纤维化模型,螺内酯干预组每天按螺内酯20 mg/kg经灌胃给药。于术后12 h、1 d、2 d、3 d、7 d、14 d和28 d处死小鼠,采用HE染色和Masson染色观察肺组织病理学变化及纤维化程度,采用real-time PCR检测各组肺组织中胶原1(Col1)、Col3、转化生长因子β(TGF-β)、单核细胞趋化蛋白1（MCP-1）及MR mRNA的表达水平。结果：（1）与对照组小鼠相比,博来霉素组及螺内酯干预组小鼠在滴注博来霉素后经历了典型的急性炎症期（12 h～3 d）、纤维化进展期（14 d）和纤维化晚期（28 d）。阻断MR下调早期炎症反应并减轻了纤维化程度。（2）螺内酯干预可以有效降低MR mRNA表达水平;阻断MR在急性炎症期显著下调MCP-1 mRNA的表达,在14 d显著下调TGF-β、Col1和Col3 mRNA表达水平。结论：(1）阻断MR可以明显减轻博来霉素诱导的肺纤维化程度;(2）阻断MR可能通过在急性炎症期调节MCP-1和TGF-β的表达,减轻炎症反应,并在纤维化进展期,下调TGF-β的表达,从而抑制肺纤维化的进展。     

肺纤维化大鼠中基质金属蛋白酶-2的表达

目的：研究基质金属蛋白酶－2（MMP2）在肺纤维化中的作用。方法：（1）用免疫组织化学方法（ABC法）观察博莱霉素所诱导的实验性大鼠纤维化肺组织内MMP2表达的动态变化;（2）用逆转录－聚合酶链反应（RT－PCR）观察博莱霉素所诱导的肺纤维化不同时期间质成纤维细胞MMP2 mRNA的动态变化。（3）用Northern印迹杂交和免疫细胞化学方法观察转化生长因子β1（TGFβ1）对体外培养的大鼠肺成纤维细胞MMP2mRNA和蛋白表达的影响。结果：（1）诱导纤维化组1－7d,病灶内浸润的单核巨噬细胞及肺泡间质细胞数量增多,MMP2免疫组织化学染色阳性,14d以后,阳性单核巨噬细胞减少,用博莱霉素28d时,阳性间质细胞亦减少。（2）博莱霉素作用后1d,肺成纤维细胞MMP2基因转录即明显增强,为对照组的2．05倍,28d时下降。（3）TGFβ1作用后,大鼠肺成纤维细胞MMP2mRNA及其蛋白表达增强。结论：肺组织内MMP2的过度表达,可能是肺纤维化启动的重要原因。     

黄芪通过抗氧化抑制博莱霉素诱导的小鼠肺纤维化

目的:研究黄芪对博莱霉素诱导的肺纤维化小鼠氧化/抗氧化水平的影响,探讨黄芪抗纤维化的可能机制。方法:将36只SPF级雌性昆明小鼠随机分为对照组(生理盐水气管内雾化)、博莱霉素组(博莱霉素3mg/kg气管内雾化)和黄芪治疗组(博莱霉素3 mg/kg气管内雾化后黄芪注射液1.7 g·kg~(-1)·d~(-1)腹腔内注射),实验第14天收集小鼠肺组织及血清标本,取小鼠肺组织行HE和Masson染色;RT-PCR法测小鼠肺组织超氧化物歧化酶(SOD)1/2/3、过氧化氢酶(CAT)、NADPH氧化酶2/4(NOX2/4)和α-平滑肌肌动蛋白(α-SMA)的mRNA水平;Western blot法测α-SMA和NOX2/4蛋白表达水平;比色法检测血清丙二醛(MDA)和总抗氧化能力(T-AOC)。结果:博莱霉素组小鼠肺组织病理损伤较正常组明显加重,α-SMA mRNA和蛋白表达,MDA/T-AOC,NOX2、NOX4和SOD3 mRNA表达,以及NOX2蛋白表达较正常组显著上升,黄芪治疗组则显著逆转上述改变;博莱霉素组小鼠NOX4蛋白表达较正常组显著下降,而黄芪治疗组较博莱霉素组显著上升;博莱霉素组和黄芪治疗组小鼠SOD1和CAT mRNA表达均较正常组显著下降;SOD2 mRNA在3个组中表达的差异无统计学显著性。结论:黄芪能够减缓博来霉素诱导的肺纤维化形成,其机制可能与调节氧化/抗氧化平衡有关。     

替普瑞酮诱导肺纤维化大鼠肺HSP70表达及干预肺纤维化的研究

目的:研究替普瑞酮(GGA)对博莱霉素(BLM)诱导的肺纤维化大鼠肺组织HSP70表达的影响及对大鼠肺纤维化的干预作用。方法:SD大鼠30只,随机分为假手术组(SO)、模型组(M)和替普瑞酮组(GGA)。M组和GGA组大鼠气管内一次性注射BLM 5 mg/kg,SO组大鼠气管内注射等体积的生理盐水。造模后第1天开始隔天灌胃给予GGA,持续到处死动物的前1天,模型组灌服等体积的生理盐水。记录大鼠每日体重,造模后第28天时处死大鼠,测定肺纤维化大鼠的肺系数、肺组织内HSP70表达及羟脯氨酸(HYP)的含量,观察肺组织病理改变。结果:GGA能提高博莱霉素处理后大鼠肺组织HSP70的表达(P<0.01);与M组相比,大鼠体重下降得到明显恢复(P<0.01),而肺组织的肺系数和羟脯氨酸(HYP)含量则明显降低(P<0.05),病理结果显示肺泡内结构完整,未出现类似M组肺组织实变现象,肺纤维化程度较轻。结论:替普瑞酮能诱导BLM肺纤维化模型大鼠肺组织HSP70表达,减轻肺纤维化程度。     

Improvement of bleomycin-induced pulmonary hypertension and pulmonary fibrosis by the endothelin receptor antagonist Bosentan

Rationale

There is evidence that endothelin plays a key role in the development of pulmonary hypertension (PH) in pulmonary fibrosis (PF). However, the functional consequence of the unselective endothelin receptor antagonist Bosentan in PH and PF has not yet been studied. Therefore, we investigated the effects of Bosentan on the development of PH in the model of Bleomycin-induced PF in rats.

Methods

Adult male Wistar rats were randomly assigned to the following groups: untreated animals (controls), Bleomycin-induced PF (Bleomycin) and Bleomycin-induced PF treated with Bosentan (Bleomycin + Bosentan). Exercise capacity was evaluated by treadmill exercise testing. PH was assessed by right ventricular systolic pressure (RVSP) and right ventricular hypertrophy. For quantification of PF the hydroxyproline content in lung tissue (HPC) was measured.

Results

Compared to controls, animals with Bleomycin-induced PF showed a significant reduction in exercise capacity (44% vs. 100%), significantly higher RVSP (65 mmHg vs. 23 mmHg), significantly more right ventricular hypertrophy (0.55 vs. 0.24) and significantly higher HPC (60.5 vs. 14.8). Bosentan treatment in animals with Bleomycin-induced PF resulted in significantly greater exercise capacity (98% vs. 44%) and a trend towards lower RVSP (52 mmHg vs. 65 mmHg), significantly less right ventricular hypertrophy (0.34 vs. 0.55) and significantly lower HPC (16.7 vs. 60.5) compared to untreated Bleomycin-induced PF.

Conclusion

Application of Bosentan in Bleomycin rats resulted in significantly higher exercise capacity as a result of improvements in PH and PF.     

大鼠肺纤维化形成中内源性一氧化氮对肺泡上皮细胞凋亡的影响

目的:研究大鼠肺纤维化形成过程中异常增多的肺内源性一氧化氮对肺泡上皮细胞凋亡的影响。方法:气管内滴注博莱霉素,用硝酸还原法检测出肺血NO₂^-/NO₃^-含量;TdT介导的dUTP缺口末端标记法(TUNEL)和透射电镜观察肺泡上皮细胞凋亡。分别观察注BLMA₅后14 d和30 d以及用氨基胍(AG)阻断iNOS合成NO后上述指标的变化。结果:(1)注BLMA₅后14 d,出肺血NO₂^-/NO₃^-含量分别高于正常对照组和注BLMA₅后30 d组(均P<0.01);凋亡的肺泡上皮细胞数亦分别多于正常对照和注BLMA₅后30 d组(均P<0.01)。(2)AG阻止出肺血NO₂^-/NO₃^-含量增高的同时,亦抑制了肺泡上皮细胞的凋亡。结论:在肺纤维化形成过程中,内源性NO的增多,有诱导肺泡上皮细胞凋亡的作用。     

Immunolocalization of cathepsin D in pneumocytes of normal human lung and in pulmonary fibrosis

Cathepsin D expression has been assessed by immunohistochemistry and immunoelectron microscopy in fetal, normal adult and injured lungs of human beings. In addition to the well known positivity of alveolar macrophages and the bronchial epithelial cells, normal type I and to a lesser extent type II pneumocytes showed a granular, cytoplasmic staining pattern. Using immunogold labelling of lowicryl embedded human lung, cathepsin D was present in lysosomes of epithelial cells. Double immunofluorescence labelling employing type I and type II specific antibodies or lectins confirmed the epithelial staining for cathepsin D. At the terminal sac period during lung development cathepsin D appears in the alveolar epithelium. In fibrotic specimens, enhanced immunoreactivity was found in epithelial and non-epithelial cells. Proliferative epithelial formations were strongly stained with cathepsin D antibodies, whereas detached, desquamated epithelial cells were weakly positive or negative. We suggest that cathepsin D plays a role in the remodelling process during fibrogenesis.     

Pathogenesis of pulmonary fibrosis induced by chrysotile asbestos

Summary A single instillation of 1 mg chrysotile B with a fiber length between 0.05 and 0.2 µm in 0.1 ml tricaprylin was made via a polyvinyl catheter into the lower lobe of the right lung of 120 six-week-old Wistar rats under anesthesia. The animals were killed at intervals between five minutes and two years. The lower lobes of the right lung were investigated by light and electron microscopy.The process of pulmonary fibrosis induced by asbestos can be subdivided into four phases: these are the phase of phagocytosis (five to 15 min), the phase of granuloma formation (between one and two weeks), the phase of septal fibrosis (between two and six months) and finally the scar stage (after one year). After instillation of small asbestos fibers into the alveoli, a major proportion of these fibers is phagocytosed by alveolar macrophages after five minutes and leaves the lungs via the airways. A proportion of the fibers penetrates through the alveolar wall (mostly conveyed by type I pneumocytes) and reaches the interstitium of the lungs. There, the fibers are taken up by pulmonary tissue macrophages and giant cells. Within the phagolysosomes, the fibers are broken down into fragments less than 0.01 µm in length. Type II pneumocytes produce surfactant in excess. These cells become necrotic, tubular myelin and lamellar bodies pass into the alveoli and into the interstitium. Surfactant is phagocytosed by resident macrophages. These macrophages phages can break down. Besides asbestos and surfactant, mediators of fibrillogenesis are released. Macrophages following up from blood monocytes ingest surfactant and asbestos. This process is perpetuated up to complete scarring. After two years, small asbestos fibers less than 0.01 µm long are present in fibroblasts and pleural mesothelia.     

Dasatinib attenuated bleomycin-induced pulmonary fibrosis in mice

Abstract

Anti-fibrotic effect of dasatinib, a platelet-derived growth factor receptor (PDGFR) and Src-kinase inhibitor, was tested on pulmonary fibrosis (PF). Adult mice were divided into four groups: mice dissected 21?d after the bleomycin (BLM) instillation (0.08?mg/kg in 200?µl) (I) and their controls (II), and mice treated with dasatinib (8?mg/kg in 100?µl, gavage) for one week 14?d after BLM instillation and dissected 21?d after instillation (III) and their controls (IV). The fibrosis score and the levels of fibrotic markers were analyzed in lungs. BLM treatment-induced cell proliferation and increased the levels of collagen-1, alpha smooth muscle actin, phospho (p)-PDGFR-alpha, p-Src, p-extracellular signal-regulated kinases1/2 and p-cytoplasmic-Abelson-kinase (c-Abl) in lungs, and down-regulated PTEN expression. Dasatinib reversed these alterations in the fibrotic lung. Dasatinib limited myofibroblast activation and collagen-1 accumulation by the inhibition of PDGFR-alpha, and Src and c-Abl activations. In conclusion, dasatinib may be a novel tyrosine and Src-kinase inhibitor for PF regression in mice.