Although considerable progress has been made in understanding the basic transport mechanisms that regulate fluid transport across the alveolar epithelium in the normal lung, it is not clear how these transport mechanisms function under pathological conditions. The experiments in this renewal application are designed to determine how alveolar epithelial fluid transport is regulated catecholamine dependent and independent mechanisms in the presence of clinically relevant causes of pulmonary edema.
Aim 1 will define the effect of elevated vascular hydrostatic pressure, the most common clinical cause of pulmonary edema, on alveolar epithelial fluid clearance. The studies will be done using a novel in situ perfused rat lung model that will provide continuous measurement of alveolar fluid clearance by a fluorescence method. Studies will also be done in ventilated sheep prepared to measure hemodynamics and lung lymph flow to test the hypothesis that beta-2 agonist therapy can hasten the resolution of hydrostatic pulmonary edema.
Aim 2 will determine if up- regulation of alveolar fluid transport by beta-2 adrenergic stimulation (endogenous or exogenous) can prevent or minimize alveolar flooding after fluid resuscitation following short term hemorrhagic or septic shock.
This aim will also test the hypothesis that oxidant injury to the alveolar epithelium is responsible for the inability of beta-2 adrenergic agonist stimulation to up-regulate alveolar fluid transport following severe hemorrhagic shock.
Aim 3 will investigate the contribution of alveolar epithelial type II cell proliferation as an important catecholamine- independent mechanism responsible for up-regulation of the fluid transport capacity of the alveolar epithelium. The hypothesis will be tested in the sub-acute phase following bleomycin induced lung injury in rats as well as in normal rats that receive keratinocyte growth factor, a potent alveolar type II cell mitogen. The information provided from these experimental studies should provide new strategies for accelerating the resolution of hydrostatic or increased permeability pulmonary edema in humans.
Showing the most recent 10 out of 232 publications
