In keeping with the theme of the SCOR on Pathobiology of Lung Development and Bronchopulmonary Dysplasia (BPD), this proposal will focus on the potential mechanisms leading to inflammation after lung injury. Oxidative and nitrative stresses are thought to be critical mediators of lung injury and subsequent induction of inflammatory responses. Proteins constitute a major target of reactivity for reactive oxygen (ROS) and nitrogen species (RNS) forming distinct protein adducts such as 3-nitrotyrosine-modified surfactant proteins, in particular SP-A and SP-D. These modifications have been shown to alter protein function and, more importantly, to modulate immune responses. Preliminary data indicate differential localization and expression of 3-nitrotyrosine in infant lungs with BPD. In addition, the investigators have found early increases in tracheal aspirate concentrations of hyaluronan (HA), a glycosaminoglycan previously associated with inflammation, in infants developing BPD. Further, ROS and RNS have been shown to fragment HA into lower molecular weight (LMW) forms that promote macrophage activation, cytokine gene expression and chemotaxis. Using the rodent intratracheal bleomycin model of lung injury, they will test the hypothesis that oxidative and nitrative stresses as a result of injury generate surfactant protein modifications and GAG adducts that activate and stimulate inflammatory gene expression and chemotaxis of macrophages, and thereby promote pulmonary inflammation. Using blockers of ROS/RNS, Aim 1 will determine the contribution of such stresses to the formation of modified proteins, LMW HA and inflammation after bleomycin injury. The signaling mechanisms of modified proteins and LMW HA in altering macrophage activation and chemotaxis in vitro will be examined in Aim 2. Inhaled nitric oxide (NO) has been proposed as a potential therapy to limit inflammation and fibrosis, and to promote both pulmonary vascular and bronchiolar dilatation in preterm infants at risk for developing BPD. The goal of Aim 3 is to examine the effect of inhaled NO on the formation of protein adducts, LMW HA and inflammation in the rat model. Finally, Aim 4 will determine changes in protein and GAG products in relation to the inflammatory response in both the preterm lamb model of BPD (Project 7) and, using samples obtained from the Clinical Core, in preterm infants randomized to inhaled NO therapy to limit BPD. Other interactions with SCOR projects include effects of iNO on SP-B/C expression and surfactant function (Project 1) and the role of TGF-beta in bleomycin injury (Project 4). These studies will define the mechanisms of oxidative/nitrative stresses in lung injury and inflammation that contribute to the pathogenesis of BPD.
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