肺纤维化的免疫发病学机制
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摘要
肺纤维化是各种内、外致病原引起慢性肺疾病的共同后果,以肺组织炎症和纤维化为共同病理特征,严重威胁人类健康和生命。获得性免疫反应特别是Th1、Th2反应的极化方向是肺纤维化发生和发展的关键。TLR4是介导多种内、外致病原引发急性肺损伤的主要模式识别受体,有学者认为TLR4缺失能够保护肺组织对抗多种原因,包括内毒素、化学物质、缺血-再灌注及臭氧等所导致的急性肺损伤。本文中我们主要报道了,基础的TLR4活性在化学物质诱导的急性肺损伤后促慢性炎症前转归和肺纤维化疾病中的关键作用。我们发现,遗传性和功能性阻断TLR4活性均能促进博莱霉素所致纤维化动物死亡,加剧肺部炎症、纤维化和肺功能降低；促进肺部抑制性免疫微环境的形成；抑制纤维性病灶区域组织的自噬活性及自噬相关的死亡。与之相反,激活TLR4可迅速促进慢性炎症转归,逆转已经形成的肺纤维化,通过活化TLR4信号介导的免疫反应减少动物死亡。同时,调节自噬活性能够逆转TLR4对肺纤维化及动物死亡的调节作用。以上结果高度提示,TLR4介导的基础免疫在化学物质引起的组织损伤后促炎症转归和纤维化疾病中的重要作用,这一先天免疫受体TLR4与肺部炎症转归和纤维化疾病之间的新机制联系为治疗慢性纤维增生疾病提示了一个新的治疗策略。
大量实验数据表明,嗜碱性粒细胞活化促进Th2型免疫反应,帮助DC细胞诱导Th0细胞分化成Th2细胞。本文中我们主要报道了,抑制嗜碱性粒细胞活化显著减少博莱霉素所致动物死亡,显著降低博莱霉素诱导的肺纤维化小鼠以及二氧化硅诱导的矽肺小鼠的肺部炎症评分,胶原沉积,羟脯氨酸含量以及α-SMA的蛋白表达均显著降低,改善了不同原因导致的肺部纤维化形成。同时,抑制嗜碱性粒细胞的活化能够显著逆转博莱霉素和二氧化硅所诱导肺组织Th2为主的抑制性免疫微环境的形成。提示,抑制嗜碱性粒细胞活化可能是治疗肺纤维化的新治疗策略。
Pulmonary inflammation and pulmonary fibrosis are the common pathological features of interstitial lung diseases that result from a variety of reasons. Despite the pathogenesis of fibrosis remaining as an enigma, the polarization direction of adaptive immunity, especially the Th1 and Th2 responses, are critical for both resolution and development of pulmonary fibrosis. Toll-like receptor 4 (TLR4) is a major pattern recognition receptor to mediate multiple lung pathogen-induced acute lung injury. Thus, TLR4 deficiency is found to be protective against acute lung injury caused by endotoxin, chemical agents, ischemia-reperfusion, or ozone. Here we report that basal TLR4 activity is crucial in the pro-resolution of chronic inflammation and tissue fibrosis after chemical agent-induced acute lung and heart injury. We found that genetic or pharmacologic inhibition of TLR4 significantly increased the bleomycin-induced animal death and aggravated pulmonary inflammation, fibrosis, and lung function because TLR4 antagonism promoted the formation of immunosuppressive tissue microenvironment, which resulted in a suppression of autophagy and autophagy-associated cell death in the fibrotic tissue. In contrast, pharmacological activation of TLR4 resulted in a quick resolution of chronic inflammation, reversed the established pulmonary fibrosis, and rescued mice from death through activating the TLR4-mediated immune responses. TLR4 activity was also critical for the resolution of cardiac inflammation and fibrosis in doxorubicin-induced dilated cardiomyopathy. Importantly, regulation of autophagy could reverse TLR4-regulated lung fibrosis and animal death. These results highlight a pivotal role for TLR4-mediated basal immunity in the pro-resolution of inflammation and fibrosis in chemical agent-mediated tissue injury and that this novel mechanistic links among innate immune receptor TLR4 and the resolution of inflammation and fibrosis suggest a novel therapeutic strategy against chronic fibroproliferative diseases.
Recent researches highlight that activated Basophils in vivo can provide initial signal to promote Th2 predominant response and help dendritc cells to determine the differentiation of Th2 cells. Also, the activation of basophils contributes to the pathogenesis of Th2-type of diseases, such as helminth infection, allergy, and chronic idiopathic urticaria. Therefore, we wonder if the basophils play a critical role in the development and resolution of pulmonary fibrosis. Our results indicated that inhibition of activation of basophils significantly attenuated the bleomycin-induced and SiO2-induced animal death, pulmonary inflammation and fibrosis, reversed BLM-induced and SiO2-induced immunosuppressive microenvironments in lungs. This study suggests that activation of basophils might be the main reason of pulmonary fibrosis.
大量实验数据表明,嗜碱性粒细胞活化促进Th2型免疫反应,帮助DC细胞诱导Th0细胞分化成Th2细胞。本文中我们主要报道了,抑制嗜碱性粒细胞活化显著减少博莱霉素所致动物死亡,显著降低博莱霉素诱导的肺纤维化小鼠以及二氧化硅诱导的矽肺小鼠的肺部炎症评分,胶原沉积,羟脯氨酸含量以及α-SMA的蛋白表达均显著降低,改善了不同原因导致的肺部纤维化形成。同时,抑制嗜碱性粒细胞的活化能够显著逆转博莱霉素和二氧化硅所诱导肺组织Th2为主的抑制性免疫微环境的形成。提示,抑制嗜碱性粒细胞活化可能是治疗肺纤维化的新治疗策略。
Pulmonary inflammation and pulmonary fibrosis are the common pathological features of interstitial lung diseases that result from a variety of reasons. Despite the pathogenesis of fibrosis remaining as an enigma, the polarization direction of adaptive immunity, especially the Th1 and Th2 responses, are critical for both resolution and development of pulmonary fibrosis. Toll-like receptor 4 (TLR4) is a major pattern recognition receptor to mediate multiple lung pathogen-induced acute lung injury. Thus, TLR4 deficiency is found to be protective against acute lung injury caused by endotoxin, chemical agents, ischemia-reperfusion, or ozone. Here we report that basal TLR4 activity is crucial in the pro-resolution of chronic inflammation and tissue fibrosis after chemical agent-induced acute lung and heart injury. We found that genetic or pharmacologic inhibition of TLR4 significantly increased the bleomycin-induced animal death and aggravated pulmonary inflammation, fibrosis, and lung function because TLR4 antagonism promoted the formation of immunosuppressive tissue microenvironment, which resulted in a suppression of autophagy and autophagy-associated cell death in the fibrotic tissue. In contrast, pharmacological activation of TLR4 resulted in a quick resolution of chronic inflammation, reversed the established pulmonary fibrosis, and rescued mice from death through activating the TLR4-mediated immune responses. TLR4 activity was also critical for the resolution of cardiac inflammation and fibrosis in doxorubicin-induced dilated cardiomyopathy. Importantly, regulation of autophagy could reverse TLR4-regulated lung fibrosis and animal death. These results highlight a pivotal role for TLR4-mediated basal immunity in the pro-resolution of inflammation and fibrosis in chemical agent-mediated tissue injury and that this novel mechanistic links among innate immune receptor TLR4 and the resolution of inflammation and fibrosis suggest a novel therapeutic strategy against chronic fibroproliferative diseases.
Recent researches highlight that activated Basophils in vivo can provide initial signal to promote Th2 predominant response and help dendritc cells to determine the differentiation of Th2 cells. Also, the activation of basophils contributes to the pathogenesis of Th2-type of diseases, such as helminth infection, allergy, and chronic idiopathic urticaria. Therefore, we wonder if the basophils play a critical role in the development and resolution of pulmonary fibrosis. Our results indicated that inhibition of activation of basophils significantly attenuated the bleomycin-induced and SiO2-induced animal death, pulmonary inflammation and fibrosis, reversed BLM-induced and SiO2-induced immunosuppressive microenvironments in lungs. This study suggests that activation of basophils might be the main reason of pulmonary fibrosis.
引文
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