This proposal focuses on the role of the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and the pulmonary collectins SP-A and SP-D in inflammation and Bronchopulmonary Dysplasia (BPD) in baboon models of preterm birth and ventilation. Data from our laboratory, using the rodent model of bleomycin-induced lung injury, indicates increased lung HA in association with macrophage accumulation. Administration of HA-binding peptide to bleomycin-injured animals decreases inflammation and fibrosis. In addition, we have found increases in tracheal aspirate HA concentrations that correlate with inflammation and are predictive of death or BPD in human preterm infants with lung disease. Oxidative and nitrative stresses are critical mediators of lung injury and inflammation. 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. 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. Preliminary data indicate differential localization and expression of 3-nitrotyrosine in rodent lungs injured with bleomycin and infant lungs with BPD. The Program for Collaborative Research on BPD provides a unique opportunity to test the mechanistic contribution of HA and pulmonary collectins to the development of BPD. Using the baboon models of BPD, we will test the hypothesis that elevated concentrations of LMW HA and post-translational modification of pulmonary collectins, occurring as a result of oxidative, nitrative and nitrosative stresses associated with preterm birth and ventilation, are integral to and promote the inflammatory process that precedes the development of BPD. Therapies that limit the production or effects of LMW HA and modified collectins will limit the incidence and/or severity of BPD.
Aim 1 will characterize the developmental and postnatal expression of HA and its receptors in relation to inflammation and markers of oxidation, nitration and nitrosylation in the baboon models.
Aim 2 will focus on determining surfactant composition, content and function, as well as the changes in oxidation, nitration and nitrosylation of SP-A and SP-D in the baboon models.
Aim 3 will examine the effects of potential therapies, including SOD mimetics, inhaled NO and HA-binding peptides on the inflammatory, HA and surfactant changes in the baboon BPD models. The experiments described in this proposal will define the contribution of LMW HA and pulmonary collectins to the outcomes of these models and are a pre-requisite to further development of novel HA-based therapeutics to limit the incidence and/or severity of BPD in humans.
|Cui, Zheng; Liao, Jie; Cheong, Naeun et al. (2018) The Receptor for Hyaluronan-Mediated Motility (CD168) promotes inflammation and fibrosis after acute lung injury. Matrix Biol :|
|Liao, Jie; Kapadia, Vishal S; Brown, L Steven et al. (2015) The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia. Nat Commun 6:8977|
|Ballard, Philip L; Gonzales, Linda W; Godinez, Rodolfo I et al. (2006) Surfactant composition and function in a primate model of infant chronic lung disease: effects of inhaled nitric oxide. Pediatr Res 59:157-62|