Injury to the pulmonary surfactant is considered a key element in the development of Adult Respiratory Distress Syndrome-type injury. Based on existing evidence in the literature and our own preliminary data, we concluded that contrary to previous belief, injury to the pulmonary surfactant system in vivo in a variety of pathological conditions, cannot be attributed solely to reactive oxygen species. Instead, we hypothesize that peroxynitrite (ONOO), produced by the chemical reaction of nitric oxide (-NO) with endogenous superoxide (O2-), play a key and central role in the initiation and propagation of alveolar epithelial injury during -NO inhalation. We have thus designed a series of integrated physiological biochemical, biophysical and cell biology studies to define the fundamental mechanisms by which NO-derived species injure the mammalian alveolar epithelium and the pulmonary surfactant system both in vivo and in vitro. This goal will be tested by fulfilling the following Specific Aims: (1). Quantify the relative extent to which O2-, -NO, ONOO-, add secondary products derived from activated alveolar macrophages chemical generators of these reactive species, or exposure to gaseous -NO, inhibit the surface active properties of surfactant and surfactant replacement mixtures; (2) examine the contribution of these reactive species in surfactant lipid and apoprotein (SP-A, SP-B and SP-C) injury and determine the extent to which this injury alters apoprotein and surfactant function; (3) define mechanisms of O2-,-NO and ONOO--mediated inhibition of alveolar type II (ATII) cell surfactant secretion and (4) assess the development and progression of injury to pulmonary surfactant and alveolar epithelium in vivo during exposure of rabbits to inhaled -NO and hyperoxia. Completion of these Specific Aims will reveal fundamental knowledge about novel mechanisms mediating oxidant and -NO injury to the alveolar epithelium and pulmonary surfactant. Fresh insight in the potential toxicity of the recently described signal transducing and therapeutic agent, -NO will provide the rational basis for devising strategies for limiting its toxicity, thus enhancing its clinical use as a vasodilatory agent.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL051173-01A1
Application #
2227742
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1994-07-01
Project End
1999-05-31
Budget Start
1994-07-01
Budget End
1995-05-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Sieck, Gary C; Ferreira, Leonardo F; Reid, Michael B et al. (2013) Mechanical properties of respiratory muscles. Compr Physiol 3:1553-67
Zarogiannis, Sotirios G; Filippidis, Aristotelis S; Fernandez, Solana et al. (2013) Nano-TiO? particles impair adhesion of airway epithelial cells to fibronectin. Respir Physiol Neurobiol 185:454-60
Song, Weifeng; Wei, Shipeng; Zhou, Yongjian et al. (2010) Inhibition of lung fluid clearance and epithelial Na+ channels by chlorine, hypochlorous acid, and chloramines. J Biol Chem 285:9716-28
Chen, Lan; Song, Weifeng; Davis, Ian C et al. (2009) Inhibition of Na+ transport in lung epithelial cells by respiratory syncytial virus infection. Am J Respir Cell Mol Biol 40:588-600
Lazrak, Ahmed; Nita, Izabella; Subramaniyam, Devipriya et al. (2009) Alpha(1)-antitrypsin inhibits epithelial Na+ transport in vitro and in vivo. Am J Respir Cell Mol Biol 41:261-70
Song, Weifeng; Liu, Gang; Bosworth, Charles A et al. (2009) Respiratory syncytial virus inhibits lung epithelial Na+ channels by up-regulating inducible nitric-oxide synthase. J Biol Chem 284:7294-306
Chen, Lan; Bosworth, Charles A; Pico, Tristant et al. (2008) DETANO and nitrated lipids increase chloride secretion across lung airway cells. Am J Respir Cell Mol Biol 39:150-62
Janciauskiene, Sabina; Nita, Izabela; Subramaniyam, Devipriya et al. (2008) Alpha1-antitrypsin inhibits the activity of the matriptase catalytic domain in vitro. Am J Respir Cell Mol Biol 39:631-7
Davis, Ian C; Matalon, Sadis (2007) Epithelial sodium channels in the adult lung--important modulators of pulmonary health and disease. Adv Exp Med Biol 618:127-40
Hickman-Davis, Judy M; McNicholas-Bevensee, Carmel; Davis, Ian C et al. (2006) Reactive species mediate inhibition of alveolar type II sodium transport during mycoplasma infection. Am J Respir Crit Care Med 173:334-44

Showing the most recent 10 out of 14 publications