Pulmonary complications are the major cause of death in fire related injuries. The pulmonary injury may be due to smoke inhalation, circulating factors released by burned skin or organs, or the combination of these. The chemical toxins in smoke and not heat are the injurious agents. There is often a lag phase between the fire and the onset of lung injury such as pulmonary edema or ARDS during which time inflammatory mediators may have to build up to cause the lung damage. In this proposal the hypothesis is that smoke induced lung injury is not by the same pathways that produce lung injury in skin burn injury, i.e. complement activation, leukostasis and aggregation, 02 free radical release and arachidonic acid activation. Certainly some of these mechanisms are involved but we feel that airway cells such as the macrophage or the epithelial cells may be the sources of the mediators of inflammation that overtime magnify the extent of the original smoke insult perhaps by attracting granulocytes. This proposal then will address the pathophysiology, cellular biology and molecular biology of smoke in comparison to cutaneous burn induced pulmonary injury. To address our hypothesis we have developed the techniques of administering to experimental animals real smoke with its multiple toxins (varying in content depending on substrate), synthetic smoke containing large (4mu) or small (0.12mu) soot plus a single smoke toxin such as acrolein or other toxins known to be in smoke. We can monitor the physiologic impact of these smokes with or without associated cutaneous burn on 1) alveolar permeability by monitoring clearance of aerosolized 99mTcDTPA or 2) vascular injury by thermal dilution or by monitoring lymph flow and content of protein and mediators of inflammation (Substance P, IL-1, TNFa or leukotrienes) in the sheep lung lymphatics, or 3) airway function by monitoring airway pressures and assessing airway histology. We culture alveolar macrophages, squamous epithelial cells, vascular smooth muscle and endothelial cells in special chambers in which we can expose them to real smoke or various synthetic smoke toxins and determine which cells release the mediators of inflammation (IL-1 and TNFa) and how the smokes induce changes in mRNA to allow this to happen. We do endothelial binding assays for leukocytes in response to smoke and smoke toxins. We have developed a low dose of cotton and of acrolein-carbon smoke that produce an increase in lung lymph flow but no detectable pulmonary edema over 18 hrs. We thus feel we have the potential to fully explore how and what in smoke causes lung injury and how this compares to and is amplified by cutaneous burns, with a goal of developing effective therapy to prevent lung complications in fire victims.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Massachusetts General Hospital
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Hales, C A; Elsasser, T H; Ocampo, P et al. (1997) TNF-alpha in smoke inhalation lung injury. J Appl Physiol 82:1433-7
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