Immunoetiology Of Pulmonary Fibrosis

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.