The pulmonary hypertensive response to chronic hypoxia varies markedly among mammalian species. An explanation for this variability was sought by exposing seven species to hypobaric hypoxia (PB equal to 435 mmHg) for 19-48 days. Control animals were studied at 1,600 m (PB equal to 630 mmHg). The pulmonary hypertension that developed varied in the following order of decreasing severity: calf and pig (severe); rat and rabbit (moderate); sheep, guinea pig, and dog (mild). Right ventricular hypertrophy developed in proportion to the elevation in right ventricular systolic pressure. These interspecies variations in response were not correlated with the degree of arterial hypoxemia, degree of polycythemia, elevation in heart rate, or postnatal age. However, the medial thickness of the small pulmonary arteries in control animals was highly correlated with the development of pulmonary hypertension and right ventricular hypertrophy in hypoxic animals. Thus, the amount of lung vascular smooth muscle inherent within each species is a major determinant of the pulmonary hypertensive response to high altitude and contributes to the interspecies variability in this response.

Single, preexposure, parenteral uijection with both recombinant tumor necrosis factor/cachectin (TNF/C) and interleukin-1 (IL-1) prolonged the survival of rats (144±9 h) in continuous hyperoxia (> 99% 02 at 1 atm) when compared with rats injected with boiled TNF/C and boiled IL-1 (61±2 h), TNF/C alone (61±2 h), IL-1 alone (62±2 h), or saline (64±3 h). After exposure to hyperoxia for 52 h, pleural effusion volume, pulmonary artery pressure, total pulmonary resistance, and lung morphologic damage were decreased in those rats given TNF/C and IL-1 as compared with saline-injected rats. In parallel, ratios of reduced (GSH) to oxidized (GSSG) glutathione were greater (P < 005) in lungs of TNF/C + IL-i-injected rats (91±20) than of salineinjected rats (30±4) that had been exposed to hyperoxia for 52 h. No differences were found in superoxide dismutase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, or catalase activities in lungs of TNF/C + IL-1-or saline-treated, hyperoxia-exposed rats. Our results indicate that pretreatment with TNF/C and IL-1 favorably altered lung glutathione redox status, decreased lung injury, and enhanced survival of rats exposed to hyperoxia.

Monocrotaline induces microvascular leak and pulmonary hypertension in rats. We have hypothesized that the leak is related in some way to the pulmonary hypertension and precedes it. In rats given 40 mg monocrotaline/kg body wt subcutaneously, lung wet weight-to-dry weight ratios and lung albumin content began to increase within the first 3 days and became maximal at 1 wk. Alveolar lavage fluid showed little or no increase in protein. Right ventricular hypertrophy increased progressively from 2 through 3 wk. An increase in lung dry weight paralleled the right ventricular hypertrophy. The amount of blood retained in the lung did not account for the increased lung water, albumin, or weight. We considered that microvascular leak without leak into the alveolar space preceded pulmonary hypertension, right ventricular hypertrophy, and increased lung dry weight. In rats not given monocrotaline but exposed for 3 wk to hypobaric hypoxia, lung albumin, lung dry weight, and right ventricular weight increased. Increased lung dry weight probably reflects hyperplasia of lung cells. If so, an association of microvascular leak, lung cell hyperplasia, and right ventricular hypertrophy may occur in both monocrotaline- and hypoxia-induced pulmonary hypertension.

Changes in the density and distribution of pulmonary mast cells were determined in six mammalian species exposed to hypobaric hypoxia (PB = 435 Torr) for 19-48 days. Control animals were studied at 1,600 m (PB = 635 Torr). Total lung mast cell hyperplasia was observed only in calves exposed to high altitude. Pigs, rats, and sheep exhibited small, but insignificant, increases in mast cell density. Perivascular mast cell proliferation adjacent to vessels of 30-500 mum in diameter was seen in both calves and pigs. Bronchial, alveolar septal, and systemic tissue (tongue) mast cell hyperplasia was not observed in any of the species. Three indices of pulmonary hypertension (right ventricular hypertrophy, medial thickness of pulmonary arteries, and pulmonary arterial pressure) correlated with perivascular mast cell density. The findings indicate that perivascular mast cell proliferation may relate more to the morphological pulmonary vascular changes and to pulmonary hypertension than to hypoxia, leading to the speculation that mast cells increase in number in response to the hypertension, rather than to mediate and maintain the hypertension.

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