Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion.
The mechanisms contributing to hypoxia in lung contusion (LC) remain unclear and not temporally associated with the peak onset of acute inflammation. We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. In addition, the role of antioxidants in reversing this process was examined. PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a nitric oxide synthase (NOS) inhibitor, L-nitro arginine (10(-3) M), or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT), or both (L-nitro arginine + SOD/CAT). Rings were constricted with norepinephrine and relaxed with an NOS agonist (A23187) or NO donor (SNAP [S-nitrosyl amino penicillamine]). Immunochemical and mass spectrometric quantification for nitrotyrosine was performed. Rats were hypoxemic at 4 h after contusion compared with controls, but recovered by 24 h (PaO(2)/FIO(2) ratio: baseline, 443 ± 28; 4 h, 288 ± 46; and 24 h, 417 ± 23). Pulmonary arterial constriction to NOS inhibition and relaxation to A23187 were impaired 4 h after LC. Pulmonary arterial relaxation to SNAP was decreased at 4 and 24 h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA were upregulated, and soluble guanylyl cyclase mRNA was downregulated 24 h after LC. Immunohistochemistry and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4 h following LC consistent with superoxide generation and formation of peroxynitrite. Collectively, these data suggest that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC.
Department of Pediatrics, University at Buffalo, Buffalo, NY, USA.
Satyan
S
Lakshminrusimha
Madathilparambil V
MV
Suresh
Paul R
PR
Knight
Sylvia F
SF
Gugino
Bruce A
BA
Davidson
Jadwiga D
JD
Helinski
Lori C
LC
Nielsen
James A
JA
Russell
Bi
B
Yu
Lixia
L
Zeng
Subramaniam
S
Pennathur
Krishnan
K
Raghavendran
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002245:Carbon Dioxide / Q000097:blood; D003288:Contusions / Q000378:metabolism / Q000503:physiopathology*; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D055370:Lung Injury / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D011014:Pneumonia / Q000378:metabolism / Q000503:physiopathology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D046509:Tissue Culture Techniques; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D012333:RNA, Messenger; D002245:Carbon Dioxide; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D010100:Oxygen