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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Specialized Center--Cooperative Agreements (U54)
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University of Colorado Denver
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