Despite two decades of research, no specific therapy has emerged for the adult respiratory distress syndrome or similar syndromes. We believe that since pulmonary edema is in fact the principal abnormality, it is still important to study the pathophysiology of pulmonary edema and to seek methods which limit excess extravascular lung water (EVLW) accumulation or hasten its resolution. To date, the only effective technique to limit EVLW accumulation is to reduce pulmonary microvascular pressure (PBF). However, maneuvers which reduce Pmv (e.g. diuretics) also carry the risk of compromising cardiac output. Therefore, other non-systemic, lung """"""""specific"""""""" approaches would be useful. Our hypothesis is that manipulating regional pulmonary blood flow PVF after acute lung injury can favorably affect the accumulation and resolution of pulmonary edema. To study this hypothesis, we have developed and validated uniquely useful new methods for measuring PBF, EVLW, and vascular permeability to proteins (as an index of injury) using the nuclear medicine imaging technique of positron emission tomography(PET). We have developed methods to correlate these data with histologic and biochemical measurements. Recently, we have regional PBF after one form of experimental acute lung injury. Thus, the major specific aim of this grant renewal is to evaluate each component of this physiologic model. Studies, are designed to evaluate a) the role of eicosanoids, b) the role of vascular obstruction, c) the role of oxygen radical formation after re-perfusion, and d) the effects of perfusion redistribution on EVLW accumulation or resolution. A second specific aim is to further develop and extend our PET methodology by a) performing a series of computer simulations concerning the PBF model, b) developing a technique to measure bronchial blood flow and evaluate its importance in modifying EVLW, and c) developing techniques to evaluate lung metabolic function as an early index of or predictor of resolution from acute lung injury. The studies described in this application are designed to make use of the special strengths of correlating PET , non-PET physiologic, biochemical and histologic data. The results will provide new information about the physiology of acute lung injury and may well suggest novel approaches to therapy.
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