Abstract
Even with remarkable advances in the care of preterm infants, chronic lung disease in the form of bronchopulmonary dysplasia (BPD) continues to be a significant pathologic consequence of prematurity. BPD is caused by the interruption of physiologic lung development and exposure of the immature newborn lung to high O2 tensions. BPD is characterized by a simplified alveolar structure, arrested lung growth, impaired vascular development and lung fibrosis (1). To identify effective treatment strategies for BPD, it is important to understand the molecular mechanisms underlying this disorder. MicroRNAs (miRNA, miR) are known to regulate growth, development and repair of the developing lung; whereas, dysregulation of miRNA expression has been associated with pulmonary disease. Specifically, members of the miR-29 family have been linked to pulmonary cancers, fibrosis, and BPD. Previous studies from our laboratory indicate that developmental induction of miR-29 expression in the fetal lung near term serves a key role in promoting surfactant-producing type II cell differentiation and function through repression of TGF-β2 signaling (2). To understand the role of miR-29 in protection against BPD, in the present study, we created mice in which the entire miR-29 family (miR-29a/b1 and miR-29b2/c) (miR-29 dKO) was disrupted. Upon exposure of miR-29 dKO and WT neonatal mice to hyperoxia (95% O2) for 5 days immediately after birth, expression levels of the proinflammatory cytokines and chemokines, IL-1 β, TGF-β1, CXCL2 and IL-6, were significantly increased in the lungs of miR-29 dKO mice, compared to WT. Furthermore, lungs of miR-29 dKO adult mice manifested increased expression of their direct targets, TGF-β2 and TGF-β3. This was associated with increased collagen deposition, as evidenced by enhanced trichrome staining, suggesting the development of lung fibrosis. HDAC4 (a direct target of miR-29) and proinflammatory TNF-α, which have been implicated in pulmonary fibrosis, also were upregulated in the lungs of miR-29 dKO mice. Overall, our studies suggest a key role of the miR-29 family and its targets in prevention of inflammatory and profibrotic signaling in the neonatal lung leading to lung pathology.
Supported by: NIH R01-HL050022 (C.R.M.)
References: (1)Michael, Zoe, et al. “Bronchopulmonary dysplasia: an update of current pharmacologic therapies and new approaches.” Clinical Medicine Insights: Pediatrics 12 (2018): 1179556518817322.(2)Guo, Wei, Houda Benlhabib, and Carole R. Mendelson. “The microRNA 29 family promotes type II cell differentiation in developing lung.” Molecular and cellular biology 36.16 (2016): 2141-2141.
Role of Type II Pneumocyte Senescence in Radiation-Induced Lung Fibrosis
