TY - JOUR
T1 - Pulmonary vascular thrombosis in rats exposed to inhaled sulfur mustard
AU - McGraw, Matthew D.
AU - Osborne, Christopher M.
AU - Mastej, Emily J.
AU - Di Paola, Jorge A.
AU - Anderson, Dana R.
AU - Holmes, Wesley W.
AU - Paradiso, Danielle C.
AU - Garlick, Rhonda B.
AU - Hendry-Hofer, Tara B.
AU - Rancourt, Raymond C.
AU - Smith, Russell W.
AU - Burns, Carol
AU - Roe, Gates B.
AU - Rioux, Jacqueline S.
AU - White, Carl W.
AU - Veress, Livia A.
N1 - Funding Information:
The authors thank the following people for their contributions to our study: Steven Abman, MD, from the Department of Pediatrics, Pulmonary Medicine, at the University of Colorado for his expert advice and guidance regarding the development of pulmonary hypertension and methodologies in barium perfused CT angiograms. They also thank their External Advisory Committee members from the Countermeasures against Chemical Threats Research Network, for their support and advice. Last, the authors would like to thank Natalie Serkova PhD and Kendra Huber of the UCCC/CTSA, Animal Imaging Shared Resources (AISR) on grants UCCC P30 and CCTSI U01 for their expert guidance and assistance with the CT barium perfusion angiograms. The authors are also grateful to Joan Loader for additional technical assistance. CounterACT Program, National Institutes of Health (NIH), Office of the Director, and the National Institute of Environmental Health Sciences (NIEHS) (1U54 ES027698-01 to C.W.W. and L.A.V.; 5U54 ES015678-09 to C.W.W.). NIH (T32HL 007670-27 To M.D.M.).
Publisher Copyright:
© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - Sulfur mustard (SM) is a chemical warfare agent. When inhaled, SM causes significant injury to the respiratory tract. Although the mechanism involved in acute airway injury after SM inhalation has been well described previously, the mechanism of SM's contribution to distal lung vascular injury is not well understood. We hypothesized that acute inhalation of vaporized SM causes activated systemic coagulation with subsequent pulmonary vascular thrombi formation after SM inhalation exposure. Sprague Dawley rats inhaled SM ethanolic vapor (3.8mg/kg). Barium/gelatin CT pulmonary angiograms were performed to assess for pulmonary vascular thrombi burden. Lung immunohistochemistry was performed for common procoagulant markers including fibrin(ogen), von Willebrand factor, and CD42d in control and SM-exposed lungs. Additionally, systemic levels of D-dimer and platelet aggregometry after adenosine diphosphate- and thrombin-stimulation were measured in plasma after SM exposure. In SM-exposed lungs, chest CT angiography demonstrated a significant decrease in the distal pulmonary vessel density assessed at 6 h postexposure. Immunohistochemistry also demonstrated increased intravascular fibrin(ogen), vascular von Willebrand factor, and platelet CD42d in the distal pulmonary vessels ( < 200 μm diameter). Circulating D-dimer levels were significantly increased (p < .001) at 6, 9, and 12 h after SM inhalation versus controls. Platelet aggregation was also increased in both adenosine diphosphate - (p < .01) and thrombin- (p < .001) stimulated platelet-rich plasma after SM inhalation. Significant pulmonary vascular thrombi formation was evident in distal pulmonary arterioles following SM inhalation in rats assessed by CT angiography and immunohistochemistry. Enhanced systemic platelet aggregation and activated systemic coagulation with subsequent thrombi formation likely contributed to pulmonary vessel occlusion.
AB - Sulfur mustard (SM) is a chemical warfare agent. When inhaled, SM causes significant injury to the respiratory tract. Although the mechanism involved in acute airway injury after SM inhalation has been well described previously, the mechanism of SM's contribution to distal lung vascular injury is not well understood. We hypothesized that acute inhalation of vaporized SM causes activated systemic coagulation with subsequent pulmonary vascular thrombi formation after SM inhalation exposure. Sprague Dawley rats inhaled SM ethanolic vapor (3.8mg/kg). Barium/gelatin CT pulmonary angiograms were performed to assess for pulmonary vascular thrombi burden. Lung immunohistochemistry was performed for common procoagulant markers including fibrin(ogen), von Willebrand factor, and CD42d in control and SM-exposed lungs. Additionally, systemic levels of D-dimer and platelet aggregometry after adenosine diphosphate- and thrombin-stimulation were measured in plasma after SM exposure. In SM-exposed lungs, chest CT angiography demonstrated a significant decrease in the distal pulmonary vessel density assessed at 6 h postexposure. Immunohistochemistry also demonstrated increased intravascular fibrin(ogen), vascular von Willebrand factor, and platelet CD42d in the distal pulmonary vessels ( < 200 μm diameter). Circulating D-dimer levels were significantly increased (p < .001) at 6, 9, and 12 h after SM inhalation versus controls. Platelet aggregation was also increased in both adenosine diphosphate - (p < .01) and thrombin- (p < .001) stimulated platelet-rich plasma after SM inhalation. Significant pulmonary vascular thrombi formation was evident in distal pulmonary arterioles following SM inhalation in rats assessed by CT angiography and immunohistochemistry. Enhanced systemic platelet aggregation and activated systemic coagulation with subsequent thrombi formation likely contributed to pulmonary vessel occlusion.
KW - CT angiography
KW - Hypercoagulability
KW - Inhalation injury
KW - Sulfur mustard
KW - Thrombosis
UR - http://www.scopus.com/inward/record.url?scp=85030717784&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfx151
DO - 10.1093/toxsci/kfx151
M3 - Article
C2 - 28962529
AN - SCOPUS:85030717784
VL - 159
SP - 461
EP - 469
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 2
ER -