Chronic hypoxia leads to abnormal pulmonary arterial remodeling (PAR) and inhibition of alveolar development (IAD) in the developing lung. Transforming growth factor-beta (TGF-(), a peptide growth factor that is a key regulator of lung development and vascular remodeling, may be a crucial mediator in the pathogenesis of PAR and IAD. TGF-( is synthesized as an inactive precursor, and activation of TGF-( is the critical step necessary to elicit biological effects. TGF-( activation is inhibited by fibroblasts in the lung which express the cell surface glycoprotein Thy-1. We have recently shown that newborn mice with disruption of TGF-( signaling due to inducible dominant negative TGF-( type II receptors (DN2RII) have attenuated IAD and PAR, indicating that TGF-( signaling is important in IAD and PAR. We have shown that hypoxia reduces Thy-1 and increases active TGF-( in newborn mice, suggesting that hypoxia-induced decreases in Thy-1 may permit increased TGF-( activation. Our laboratory has made the novel observations that Thy-1 null mice have IAD and increased phospho-Smad2, (-smooth muscle actin, interstitial collagen, tissue lung resistance (but normal airway resistance), and decreased lung compliance, demonstrating that absence of Thy-1 in the developing lung leads to a lung phenotype similar to bronchopulmonary dysplasia (BPD). Our preliminary data indicate that TGF-( synthesis may be regulated by endothelin-1 (ET-1), a known mediator of PAR. The objective of this project is to determine the mechanisms by which hypoxic exposure during lung development leads to increased TGF-( activation and subsequent PAR and IAD.
Specific Aim 1 will test the hypothesis that TGF-( signaling is necessary for hypoxia-induced PAR and IAD.
Specific Aim 2 will assess the mechanistic role of Thy-1 in TGF-( activation and the pathogenesis of IAD in the presence or absence of hypoxia.
Specific Aim 3 will test the specific hypothesis that hypoxia-induced increases in ET-1 stimulate TGF-( synthesis and activation. A vertically-integrated approach, with in vivo models (newborn mice exposed to hypoxia or air for 2 weeks from birth) and in vitro models (neonatal murine pulmonary arterial smooth muscle cells and fibroblasts) will be used. Currently available transgenic mice (Thy-1 null, DN2RII, (6 integrin null), in addition to wild-type mice will be used to characterize the critical signaling pathways. PAR contributes to persistent pulmonary hypertension of the newborn (PPHN), and both IAD and PAR are seen in BPD. The incidence of PPHN and BPD remains high despite advances in neonatal care, and new paradigms are essential for the development of novel therapeutic strategies. The experiments outlined in this proposal will increase our knowledge of the mechanisms responsible for normal and abnormal pulmonary arterial remodeling and alveolar development in the perinatal period. At a minimum, these studies will determine the role of TGF-( as a key regulator of hypoxia-induced IAD and PAR. These experiments will also identify the components of TGF-( signaling pathway regulated by hypoxia, and TGF-( activators under hypoxic conditions. PROJECT NARRATIVE: Two major causes of death and morbidity in newborn infants are persistent pulmonary hypertension of the newborn (PPHN) and bronchopulmonary dysplasia (BPD), which are characterized by abnormal pulmonary arterial thickening, pulmonary hypertension, and inhibition of alveolar development. Excessive activation of transforming growth factor-beta, a protein that is important in normal lung development, may lead to the abnormal lung development that is seen in PPHN and BPD. This proposal will determine the role of transforming growth factor-beta in abnormal lung development and the mechanisms by which transforming growth factor-beta becomes activated, and may lead to the development of new treatment options for PPHN and BPD.
|Ramani, Manimaran; Bradley, Wayne E; Dell'Italia, Louis J et al. (2015) Early exposure to hyperoxia or hypoxia adversely impacts cardiopulmonary development. Am J Respir Cell Mol Biol 52:594-602|
|Sanders, Yan Y; Hagood, James S; Liu, Hui et al. (2014) Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice. Eur Respir J 43:1448-58|
|Schulz, Marcel H; Pandit, Kusum V; Lino Cardenas, Christian L et al. (2013) Reconstructing dynamic microRNA-regulated interaction networks. Proc Natl Acad Sci U S A 110:15686-91|
|Ramani, Manimaran; van Groen, Thomas; Kadish, Inga et al. (2013) Neurodevelopmental impairment following neonatal hyperoxia in the mouse. Neurobiol Dis 50:69-75|
|Ambalavanan, Namasivayam; Stanishevsky, Andrei; Bulger, Arlene et al. (2013) Titanium oxide nanoparticle instillation induces inflammation and inhibits lung development in mice. Am J Physiol Lung Cell Mol Physiol 304:L152-61|
|Xiao, Rui; Perveen, Zakia; Rouse, Rodney L et al. (2013) In utero exposure to second-hand smoke aggravates the response to ovalbumin in adult mice. Am J Respir Cell Mol Biol 49:1102-9|
|Hagood, James S; Ambalavanan, Namasivayam (2013) Systems biology of lung development and regeneration: current knowledge and recommendations for future research. Wiley Interdiscip Rev Syst Biol Med 5:125-33|
|Ramani, Manimaran; Ambalavanan, Namasivayam (2013) Feeding practices and necrotizing enterocolitis. Clin Perinatol 40:1-10|
|Zarogiannis, Sotirios G; Filippidis, Aristotelis S; Fernandez, Solana et al. (2013) Nano-TiOýýý particles impair adhesion of airway epithelial cells to fibronectin. Respir Physiol Neurobiol 185:454-60|
|Salas, Ariel A; Faye-Petersen, Ona M; Sims, Brian et al. (2013) Histological characteristics of the fetal inflammatory response associated with neurodevelopmental impairment and death in extremely preterm infants. J Pediatr 163:652-7.e1-2|
Showing the most recent 10 out of 24 publications