Sox9 Activation is Essential for the Recovery of Lung Function after Acute Lung Injury

Abstract

Background/Aims: Acute lung injury (ALI) often predisposes acute respiratory distress syndrome (ARDS) in humans, and is featured with neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Although the pathogenesis of ALI is relatively well studied, the knowledge on the molecular regulation of the post-ALI lung recovery are poorly understood. Methods: Here, we used a widely applied bleomycin-induced ALI model to study the molecular mechanisms that underlie the post-ALI lung recovery in mice. We analyzed Sox9 expression in mouse lung by RT-qPCR, Western blot and immunohistochemistry. We analyzed miR-101 levels in mouse lung by RT-qPCR. We inhibited Sox9 in mouse lung by expressing either shRNA for Sox9 or miR-101, and analyzed the effects of Sox9 suppression on lung recovery. Results: We detected a significant increase in Sox9 protein but not mRNA, and a signifcant decrease in miR-101 levels in the mouse lung after ALI. MiR-101 was found to target 3'-UTR of Sox9 mRNA to inhibit its expression. Sox9 inhibition by either shRNA for Sox9 or by miR-101 further impaired the functional recovery of the lung after ALI. Conclusion: Our data suggest that Sox9 activation is essential for the recovery of lung function after ALI, which highlights a previously unappreciated mechanism that controls the post-ALI lung recovery.

Fibrocytes Ameliorate Acute Lung Injury by Decreasing Inflammatory Cytokine and Chemokine Levels and Reducing Neutrophil Accumulation in the Lung

“…Previous results have shown that fibroproliferation is a stereotypical part of the normal repair process in ALI/ARDS, which is characterized by intra-alveolar accumulation of fibroblasts and collagen deposition [21-24]. Other reports have shown that excessive fibroproliferation is associated with poorer outcomes [23, 25]. Fibrocytes participate in bleomycin models of pulmonary fibrosis [26].…”

Heparan Sulfate and Chondroitin Sulfate Glycosaminoglycans Are Targeted by Bleomycin in Cancer Cells

“…Lung fibrosis is induced in certain cancer patients treated with BLEOMYCIN with molecular mechanisms largely unknown. Bleomycin is the mostly used chemical in inducing lung fibrosis in animal models [8, 51]. Both FGF-2 and TGF-β signaling pathways play major roles in the fibrosis process and GAGs are co-regulators of both FGF-2 and TGF-β pathways [54, 55].…”

“…Unfortunately, Bleomycin also induces lung inflammation that lead to fibrosis and rapid death in certain cancer patients. The unexplainable side effect of bleomycin makes it an effective reagent in inducing lung fibrosis in a variety of animal models [6-8]. Up to date, it is still unknown the molecular targets of bleomycin that causes lung fibrosis.…”

MicroRNAs in mucosal inflammation

“…Sox9 turned out to be a direct miR-101 target, and its suppression adequate recovery after lung injury. Therefore, appropriate epithelial Sox9 expression appears to be essential for proper lung recovery after lung injury [68]. One of the first miRNAs with a role in preventing fibrosis was identified by Pandit et al [69] .…”

“…For example miR-21 and miR-122a directly influence mucosal permeability by regulating the expression of epithelial tight junctions [62, 63]. In later stages of mucosal inflammation including the resolution, remodeling and repair processes miRNAs are also critically involved and e.g., promote adequate recovery such as miR-101 which is important for proper lung recovery after lung injury [68]. Epithelial let-7d is essential in preventing remodeling and development of pulmonary fibrosis after inflammation and lung injury [69].…”