Inhalation of toxic gases such as sulfur mustard (SM) and chlorine can cause exudative ainway damage and obstruction, inflammation and oxidative injury. Although antioxidant and antiprotease therapies may limit lung injury, most required administration concomitant with or almost immediately (<30 min) after toxic inhalation. Real worid scenarios for acts of terrorism and civilian disasters show that responders may not reach victims for some time. Thus, rescue countermeasures that are effective when started hours after exposure also are needed. Recent data in our laboratory indicates that catalytic antioxidants can limit or prevent airways damage, reactivity, and oxidative stress after SM analog CEES, SM, or chlorine when started at an hour after inhalation. Despite this, progressive ainways injury can still occur with massive toxic inhalation. Using sulfur mustard analog CEES, we identified critical roles for tissue factor (TF) and the coagulation cascade in causing obstructive airway fibrin-containing casts. These were identified by airway microdissection. By this technique, fibrin-containing casts were found in central and conducting ainways after inhalation of CEES, SM and chlorine. Our colleague, Dana Anderson, working at USAMRICD, has identified identical lesions in ainways of rats exposed to SM at that center, and these appear responsible for the firequent death of animals within the first 72 h after exposure. In vitro and in vivo studies indicate that two strategies, one pre-emptively inhibiting TF using specific antagonists, and one to lyse casts using tissue plasminogen activator (tPA), could be effective in limiting or reversing ainway occlusion, respectively. In fact, preliminary data indicate that tPA started 4 hours after toxic inhalation of CEES can still dramatically relieve ainway obstruction and normalize arterial oxygen saturation. We propose to inhibit airway coagulation both eariy and after ainway obstruction is well developed. Because coagulation and inflammation are integrally linked, both inflammation and secondary oxidative stress also could be decreased. We will examine acute exposure scenarios in rats, using CEES, SM and chlorine, with rescue therapies initiated 1-16 h after exposure. Arterial oxygen saturation is monitored noninvasively in each individual animal by pulse oximetry. At termination lungs are lavaged to measure cytokines, fibrin, and infiammation. Perfused snap-frozen lungs are used to measure oxidative stress markers. Fixed lung are used for microdissection and mapping, with morphometric assessment of ainway occlusion in central and dependent ainways. High resolution chest CT scans will be used to track progression and resolution of large ainway lesions and lung disease. Lung physiology will be measured in selected experiments. The most effective 'coagulation based'strategy(s) will be combined with catalytic antioxidant AEOL 10150 to determine if synergistic benefit can be obtained. These approaches should provide specific therapies for rescue of patients with ainway injury due to toxic gas inhalation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
3U54ES015678-08W1
Application #
8737371
Study Section
Special Emphasis Panel (ZRG1-MDCN-J)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$23,921
Indirect Cost
$2,276
Name
University of Colorado-Denver
Department
Type
DUNS #
City
State
Country
Zip Code
Tewari-Singh, Neera; Agarwal, Rajesh (2016) Mustard vesicating agent-induced toxicity in the skin tissue and silibinin as a potential countermeasure. Ann N Y Acad Sci 1374:184-92
McElroy, Cameron S; Day, Brian J (2016) Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals. Biochem Pharmacol 100:1-11
White, Carl W; Rancourt, Raymond C; Veress, Livia A (2016) Sulfur mustard inhalation: mechanisms of injury, alteration of coagulation, and fibrinolytic therapy. Ann N Y Acad Sci 1378:87-95
McElroy, Cameron S; Min, Elysia; Huang, Jie et al. (2016) From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity. Toxicol Sci 154:341-353
Houin, Paul R; Veress, Livia A; Rancourt, Raymond C et al. (2015) Intratracheal heparin improves plastic bronchitis due to sulfur mustard analog. Pediatr Pulmonol 50:118-26
Ahmad, Shama; Ahmad, Aftab; Hendry-Hofer, Tara B et al. (2015) Sarcoendoplasmic reticulum Ca(2+) ATPase. A critical target in chlorine inhalation-induced cardiotoxicity. Am J Respir Cell Mol Biol 52:492-502
Kumar, Dileep; Tewari-Singh, Neera; Agarwal, Chapla et al. (2015) Nitrogen mustard exposure of murine skin induces DNA damage, oxidative stress and activation of MAPK/Akt-AP1 pathway leading to induction of inflammatory and proteolytic mediators. Toxicol Lett 235:161-71
Goswami, Dinesh G; Kumar, Dileep; Tewari-Singh, Neera et al. (2015) Topical nitrogen mustard exposure causes systemic toxic effects in mice. Exp Toxicol Pathol 67:161-70
Veress, Livia A; Anderson, Dana R; Hendry-Hofer, Tara B et al. (2015) Airway tissue plasminogen activator prevents acute mortality due to lethal sulfur mustard inhalation. Toxicol Sci 143:178-84
Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha et al. (2015) Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin. Toxicol Appl Pharmacol 285:71-8

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