Abstract
As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
Highlights
Tissue fibrosis, defined as the excessive and persistent formation of non functional scar tissue in response to repeated injury and insult, is a leading cause of morbidity and mortality associated with organ failure in various chronic diseases such as those affecting the lung interstitium [1]
Fibrosis results from the excessive activity of fibroblasts, in particular a differentiated form known as myofibroblast that is responsible for the excessive and persistent accumulation of scar tissue and organ failure
Given the poor prognosis of Idiopathic Pulmonary Fibrosis (IPF) patients, new insights into the biology offibroblasts is of major interest to develop new therapeutics aimed at reducingfibroblast activity to slow or even reverse disease progression, thereby preserving organ function and prolonging life
Summary
Tissue fibrosis, defined as the excessive and persistent formation of non functional scar tissue in response to repeated injury and insult, is a leading cause of morbidity and mortality associated with organ failure in various chronic diseases such as those affecting the lung interstitium [1]. Among the interstitial lung diseases of unknown etiology, Idiopathic Pulmonary Fibrosis (IPF) is the most common and lethal with a median survival of 3 to 5 years after diagnosis [2]. The pathogenesis of IPF is complex and largely unknown [2], but observations based on both animal models of pulmonary fibrosis and lung sections from patients with IPF
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