Carl W. White

Sulfur mustard inhalation: mechanisms of injury, alteration of coagulation, and fibrinolytic therapy.

Acute lung injury due to sulfur mustard (SM) inhalation causes the formation of airway fibrin casts that obstruct airways at multiple levels, leading to acute respiratory failure and death. These pathophysiological effects are seen in rodent models of acute SM vapor inhalation, as well as in human victims of acute SM inhalation. In rat models, the initial steps in activation of the coagulation system at extravascular sites depend on tissue factor (TF) expression by airway cells, especially in the microparticle fraction, and these effects can be inhibited by TF pathway inhibitor protein. Not only does the procoagulant environment of the acutely injured lung contribute to airway cast formation, but these lesions persist in airways because of the activation of multiple antifibrinolytic pathways, including plasminogen activator inhibitor‐1, thrombin‐activatable fibrinolysis inhibitor, and α2‐antiplasmin. Airway administration of tissue plasminogen activator can overwhelm these effects and save lives by preventing fibrin‐dependent airway obstruction, gas‐exchange abnormalities, and respiratory failure. In human survivors of SM inhalation, fibrotic processes, including bronchiolitis obliterans and interstitial fibrosis of the lung, are among the most disabling chronic lesions. Antifibrotic therapies may prove useful in preventing either or both of these forms of chronic lung damage.

Automated 3D reconstruction and evaluation of methyl isocyanate-induced airway injury in a rat model using a miniature optical coherence endoscopy probe (Conference Presentation)

Development of effective rescue countermeasures for toxic inhaled industrial chemicals such as methyl isocyanate (MIC) has been an emerging interest. The conducting airways are especially sensitive to such chemicals, and their inhalation can cause severe airway and lung damage. In an attempt to develop an effective therapeutic agent for MIC, animal models have been evaluated with molecular diagnostics, histological examination, and arterial blood gases. However, direct measurement of the airway structure has not been performed. Our group previously demonstrated anatomical OCT scanning of human proximal airways with endoscopic probes. However, a smaller probe with diameter of less than half a millimeter is required for scanning the MIC-exposed rat trachea. In this study, we acquired volumetric scanning of MIC-exposed rat trachea using a miniature endoscopic probe and performed automated segmentation to reconstruct a 3-D structure of the intraluminal surface. Our miniature probe is 0.4 mm in diameter and based on a fully fiberoptic design. In this design, three optical fibers with core sizes of 9, 12, and 20 um replace the lens, and the angle-polished fiber at the distal end reflects the beam at a perpendicular angle and replaces the mirror. Using automated segmentation, we reconstructed the three-dimensional structure of intraluminal space in MIC-exposed rat trachea. Compared to the non-exposed rat trachea, which had a hollow tubular structure with a relatively uniform cross-section area, the MIC-exposed rat trachea showed significant airway narrowing as a result of epithelial detachment and extravascular coagulation within the airway. This technique could potentially be applied to high-throughput drug screening of animal models.