Chlorine gas exposure causes systemic endothelial dysfunction by inhibiting endothelial nitric oxide synthase-dependent signaling.
Chlorine gas (Cl(2)) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl(2) exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl(2) promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl(2) for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl(2) dose (0-400 ppm) and time after exposure (0-48 h) were determined. Exposure to Cl(2) (250-400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (∼ 60%) in aorta isolated from Cl(2)-exposed versus air-exposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl(2) exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl(2)-exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl(2) exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms.
Department of Pathology, University of Alabama at Birmingham, 35294, USA.
Jaideep
J
Honavar
Andrey A
AA
Samal
Kelley M
KM
Bradley
Angela
A
Brandon
Joann
J
Balanay
Giuseppe L
GL
Squadrito
Krishnan
K
MohanKumar
Akhil
A
Maheshwari
Edward M
EM
Postlethwait
Sadis
S
Matalon
Rakesh P
RP
Patel
D055371:Acute Lung Injury / Q000139:chemically induced* / Q000201:enzymology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002619:Chemical Warfare Agents / Q000633:toxicity; D002713:Chlorine / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D019570:Inhalation Exposure; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects
D002619:Chemical Warfare Agents; D016207:Cytokines; D012333:RNA, Messenger; D009569:Nitric Oxide; D002713:Chlorine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III