Chlorine gas exposure disrupts nitric oxide homeostasis in the pulmonary vasculature.
Exposure to chlorine (Cl2) gas during industrial accidents or chemical warfare leads to significant airway and distal lung epithelial injury that continues post exposure. While lung epithelial injury is prevalent, relatively little is known about whether Cl2 gas also promotes injury to the pulmonary vasculature. To determine this, rats were subjected to a sub-lethal Cl2 gas exposure (400 ppm, 30 min) and then brought back to room air. Pulmonary arteries (PA) were isolated from rats at various times post-exposure and contractile (phenylephrine) and nitric oxide (NO)-dependent vasodilation (acetylcholine and mahmanonoate) responses measured ex vivo. PA contractility did not change, however significant inhibition of NO-dependent vasodilation was observed that was maximal at 24-48 h post exposure. Superoxide dismutase restored NO-dependent vasodilation suggesting a role for increased superoxide formation. This was supported by ∼2-fold increase in superoxide formation (measured using 2-hydroethidine oxidation to 2-OH-E+) from PA isolated from Cl2 exposed rats. We next measured PA pressures in anesthetized rats. Surprisingly, PA pressures were significantly (∼4 mmHg) lower in rats that had been exposed to Cl2 gas 24 h earlier suggesting that deficit in NO-signaling observed in isolated PA experiments did not manifest as increased PA pressures in vivo. Administration of the iNOS selective inhibitor 1400W, restored PA pressures to normal in Cl2 exposed, but not control rats suggesting that any deficit in NO-signaling due to increased superoxide formation in the PA, is offset by increased NO-formation from iNOS. These data indicate that disruption of endogenous NO-signaling mechanisms that maintain PA tone is an important aspect of post-Cl2 gas exposure toxicity.
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Jaideep
J
Honavar
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Eddie
E
Bradley
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Kelley
K
Bradley
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Joo Yeun
JY
Oh
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Matthew O
MO
Vallejo
Department of Anesthesiology, University of Pittsburgh, PA, United States.
Eric E
EE
Kelley
Department of Anesthesiology, University of Pittsburgh, PA, United States.
Nadiezhda
N
Cantu-Medellin
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Stephen
S
Doran
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Birmingham VA Medical Center, United States.
Louis J
LJ
Dell'italia
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Centers for Free Radical Biology and Lung Injury and Repair, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Sadis
S
Matalon
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Centers for Free Radical Biology and Lung Injury and Repair, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: rakeshp@uab.edu.
Rakesh P
RP
Patel
D000818:Animals; D002713:Chlorine / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005740:Gases; D006706:Homeostasis / Q000187:drug effects*; D008168:Lung / Q000378:metabolism*; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D005740:Gases; D009573:Nitrites; D013481:Superoxides; D009569:Nitric Oxide; D002713:Chlorine; D019001:Nitric Oxide Synthase
Halogen; Inflammation; Lung