Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids.

Abstract

Pulmonary edema after ascent to altitude is well recognized but its pathogenesis is poorly understood. To determine whether altitude exposure increases lung vascular permeability, we exposed rats to a simulated altitude of -14,500 feet (barometric pressure [Pbi 450 Torr) and measured the pulmonary transvascular escape of radiolabeled '25l-albumin corrected for lung blood content with 51Cr-tagged red blood cells (protein leak index = PLI). Exposures of 24 and 48 h caused significant increases in PLI (2.30±0.08 and 2.40±0.06) compared with normoxic controls (1.76±0.06), but brief hypoxic exposures of 1-13 h produced no increase in PLI, despite comparable increases in pulmonary artery pressure. There were associated increases in gravimetric estimates of lung water in the altitude-exposed groups and perivascular edema cuffs on histologic examination. Normobaric hypoxia (48 h; fractional inspired oxygen concentration [FI021 = 15%) also increased lung transvascular protein escape and lung water.Dexamethasone has been used to prevent and treat altitude-induced illnesses, but its mechanism of action is unclear. Dexamethasone (0.5 or 0.05 mg/kg per 12 h) started 12 h before and continued during 48 h of altitude exposure prevented the hypoxia-induced increases in transvascular protein escape and lung water. Hemodynamic measurements (mean pulmonary artery pressure and cardiac output) were unaffected by dexamethasone, suggesting that its effect was not due to a reduction in pulmonary artery pressure or flow. The role of endogenous glucocorticoid activity was assessed in adrenalectomized rats that showed augmented hypoxia-induced increases in transvascular protein escape, which were prevented by exogenous glucocorticoid replacement. In summary, subacute hypoxic exposures increased pulmonary transvascular protein escape and lung water in rats. Dexamethasone prevented these changes independent of reductions of mean pulmonary artery pressure or flow, whereas adrenalectomy increased pulmonary vascular permeability and edema at altitude. Increases in vascular permeability in hypoxia could contribute to the development of high-altitude pulmonary edema and endogenous glucocorticoids may have an important influence on pulmonary vascular permeability in hypoxia. Introduction Rapid ascent to high altitude may be associated with the development of pulmonary edema (HAPE)' (1,2 Despite this, attempts to demonstrate hypoxia-induced changes in permeability in the laboratory have produced conflicting results. Bland et al. (5) and Landolt et al. (6) failed to detect increases in lung lymph flow in adult sheep during hypoxia, even with the added stress of increased blood flow. In contrast, other studies have demonstrated increases in lymph flow in newborn lambs (7) and dogs (8-10) after hypoxia. Furthermore, studies in isolated perfused dog lungs have revealed increased filtration and reflection coefficients consistent with increased vascular permeability after brief exposures to anoxic gas (1 1, 12). Differences in both species and ...

Decreased alveolar oxygen induces lung inflammation

“…Stelzner et al (30) showed in vivo increased pulmonary extravasation of albumin in rat lungs after 48 h of exposure to hypobaric hypoxia. However, short-term exposure to hypoxia (1,3,6, and 13 h) did not cause significant increases in extravasation.…”

Antecedents of Clinically Significant Pulmonary Hemorrhage Among Newborn Infants

“…In a rat model of highaltitude pulmonary edema, a dexamethasone-induced reduction in transvascular protein leak appeared to be independent of pulmonary artery pressure. 22 It is conceivable that glucocorticoids induce vascular structural or biochemical changes that make pulmonary capillaries less susceptible to stress failure. The apparent protective influence on PH of a very young GA is more challenging to explain.…”

Hypoxia and β2-Agonists Regulate Cell Surface Expression of the Epithelial Sodium Channel in Native Alveolar Epithelial Cells

“…Rapid ascent to high altitude may induce in some subjects the development of pulmonary edema. Although the initial cause of alveolar flooding is likely related to altered hemodynamics or increased lung microvascular permeability (7,8), new data from human and animal studies support the concept that defective alveolar fluid clearance could have a pathogenic role in the development of high altitude pulmonary edema (HAPE) and could be a potential target for therapy. Sartori et al (9) recently reported that HAPE-sensitive subjects at low altitude have a decrease in nasal transepithelial potential difference compared with HAPE-insensitive subjects, suggesting that these subjects may have a genetically determined impairment of transepithelial sodium and liquid clearance in the lungs.…”