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Abstract：
BACKGROUND: Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However, current treatments can only delay disease progression rather than provide a cure. The role of inflammation in PF progression is well-established, but new insights into immune regulation are fundamental for developing more efficient therapies. c-MET signaling has been implicated in the migratory capacity and effector functions of immune cells. Nevertheless, the role of this signaling pathway in the context of PF-associated lung diseases remains unexplored.
METHODS: To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases.
RESULTS: c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease.
CONCLUSIONS: These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.
METHODS: To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases.
RESULTS: c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease.
CONCLUSIONS: These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.
摘要：
背景：肺纤维化（PF）是几种与高发病率和死亡率相关的间质性肺病（ILD）的病理终末期。然而,目前的治疗只能延缓疾病进展，而不是提供治愈。炎症在PF进展中的作用是公认的，但是对免疫调节的新见解对于开发更有效的疗法至关重要。c-MET信号传导与免疫细胞的迁移能力和效应子功能有关。然而，该信号通路在PF相关肺部疾病中的作用仍未被研究.
方法：为了确定免疫细胞中c-MET在肺纤维化进展中的影响，我们在免疫细胞中使用了c-Met的条件性缺失。为了诱导肺纤维化,对小鼠气管内施用博来霉素(BLM)。在21天的过程中，评估小鼠的体重变化，在不同时间点安乐死后，评估支气管肺泡灌洗液细胞和肺组织的炎症和纤维化。此外，在冷冻活检切片中评估c-MET表达，支气管肺泡灌洗液细胞样本和单细胞RNA测序数据集来自不同间质性肺疾病的人类患者。
结果：c-MET在肺免疫细胞中被诱导表达，特别是在T细胞中，间质巨噬细胞，和中性粒细胞,在BLM诱导的PF小鼠模型的炎症阶段。免疫细胞中c-Met的缺失与BLM处理的小鼠的早期体重恢复和改善的存活率相关。此外，免疫细胞中c-Met的缺失与免疫细胞群的早期募集有关，通常被发现表达c-MET，导致随后细胞毒性和促炎环境的减弱。因此,较不广泛的炎症反应，可能伴随着组织修复,最终导致纤维化病变程度较低。此外，c-MET表达在纤维化ILD患者的肺T细胞中上调，提示c-MET可能参与纤维化疾病的发展。
结论：这些结果强调了免疫细胞中c-MET信号传导对其增强的不受控制的募集和对促炎和促纤维化表型的激活的关键贡献，导致肺损伤的加重和随之而来的纤维化的发展。
方法：为了确定免疫细胞中c-MET在肺纤维化进展中的影响，我们在免疫细胞中使用了c-Met的条件性缺失。为了诱导肺纤维化,对小鼠气管内施用博来霉素(BLM)。在21天的过程中，评估小鼠的体重变化，在不同时间点安乐死后，评估支气管肺泡灌洗液细胞和肺组织的炎症和纤维化。此外，在冷冻活检切片中评估c-MET表达，支气管肺泡灌洗液细胞样本和单细胞RNA测序数据集来自不同间质性肺疾病的人类患者。
结果：c-MET在肺免疫细胞中被诱导表达，特别是在T细胞中，间质巨噬细胞，和中性粒细胞,在BLM诱导的PF小鼠模型的炎症阶段。免疫细胞中c-Met的缺失与BLM处理的小鼠的早期体重恢复和改善的存活率相关。此外，免疫细胞中c-Met的缺失与免疫细胞群的早期募集有关，通常被发现表达c-MET，导致随后细胞毒性和促炎环境的减弱。因此,较不广泛的炎症反应，可能伴随着组织修复,最终导致纤维化病变程度较低。此外，c-MET表达在纤维化ILD患者的肺T细胞中上调，提示c-MET可能参与纤维化疾病的发展。
结论：这些结果强调了免疫细胞中c-MET信号传导对其增强的不受控制的募集和对促炎和促纤维化表型的激活的关键贡献，导致肺损伤的加重和随之而来的纤维化的发展。
