Loss Of Hypoxic Vasoconstriction Research Articles

Hypoxic pulmonary vasoconstriction, carotid body function and erythropoietin production in adult rats perinatally exposed to hyperoxia.

Adult animals that have been perinatally exposed to oxygen-rich atmospheres (hyperoxia), recalling those used for oxygen therapy in infants, exhibit a loss of hypoxic pulmonary vasoconstriction, whereas vasoconstriction elicited by depolarizing agents is maintained. Loss of pulmonary hypoxic vasoconstriction is not linked to alterations in oxygen-sensitive K(+) currents in pulmonary artery smooth muscle cells. Loss of hypoxic vasoconstriction is associated with early postnatal oxidative damage and corrected by an antioxidant diet. Perinatal hyperoxia damages carotid body chemoreceptor cell function and the antioxidant diet does not reverse it. The hypoxia-elicited increase in erythropoietin plasma levels is not affected by perinatal hyperoxia. The potential clinical significance of the findings in clinical situations such as pneumonia, chronic obstructive pulmonary disease or general anaesthesia is considered. Adult mammalians possess three cell systems that are activated by acute bodily hypoxia: pulmonary artery smooth muscle cells (PASMC), carotid body chemoreceptor cells (CBCC) and erythropoietin (EPO)-producing cells. In rats, chronic perinatal hyperoxia causes permanent carotid body (CB) atrophy and functional alterations of surviving CBCC. There are no studies on PASMC or EPO-producing cells. Our aim is to define possible long-lasting functional changes in PASMC or EPO-producing cells (measured as EPO plasma levels) and, further, to analyse CBCC functional alterations. We used 3- to 4-month-old rats born and reared in a normal atmosphere or exposed to perinatal hyperoxia (55-60% O2 for the last 5-6days of pregnancy and 4weeks after birth). Perinatal hyperoxia causes an almost complete loss of hypoxic pulmonary vasoconstriction (HPV), which was correlated with lung oxidative status in early postnatal life and prevented by antioxidant supplementation in the diet. O2 -sensitivity of K(+) currents in the PASMC of hyperoxic animals is normal, indicating that their inhibition is not sufficient to trigger HPV. Perinatal hyperoxia also abrogated responses elicited by hypoxia on catecholamine and cAMP metabolism in the CB. An increase in EPO plasma levels elicited by hypoxia was identical in hyperoxic and control animals, implying a normal functioning of EPO-producing cells. The loss of HPV observed in adult rats and caused by perinatal hyperoxia, comparable to oxygen therapy in premature infants, might represent a previously unrecognized complication of such a medical intervention capable of aggravating medical conditions such as regional pneumonias, atelectases or general anaesthesia in adult life.

Effects of methylprednisolone on lung oxygen toxicity in awake sheep.

The purpose of this study was to measure the effects of high doses of corticosteroids on the response to breathing 100% O2 in sheep. Sheep were prepared for chronic measurement of vascular pressures, cardiac output, gas exchange, and for collection of lung lymph. Tracheostomies were made for accurate delivery of gas mixtures. Eight sheep received methylprednisolone 30 mg/kg body wt every 6 h for eight doses, four for the first 48 h, and four for the final 24-48 h of 100% O2 breathing. Eight control sheep breathed 100% O2 without methylprednisolone, four sheep breathed compressed air without methylprednisolone, and two breathed compressed air and received methylprednisolone. Sheep had daily measurements of hypoxic vasoconstriction (fractional concentration of O2 in inspired gas = 0.12), gas exchange, lymph flow, and lymph and plasma protein concentration. Polymorphonuclear leukocyte (granulocyte) function in experimental and control sheep was assessed ex vivo by tests of chemotaxis, aggregation, and superoxide production. The number of granulocytes in peripheral lung was measured in biopsy tissue taken at the time of original surgery and postmortem. Methylprednisolone did not affect the time course nor magnitude of gas exchange abnormality, lymph flow and composition, loss of hypoxic vasoconstriction, lung granulocyte accumulation, nor postmortem lung water caused by 100% O2 breathing. Sheep receiving methylprednisolone had a shorter survival by several h, independent of the timing of the drug. Granulocytes from methylprednisolone-treated sheep showed normal function ex vivo by all three assays. We conclude that high doses of methylprednisolone unfavorably affect the rate and progression of lung injury in sheep breathing 100% O2.(ABSTRACT TRUNCATED AT 250 WORDS)

MECHANISMS OF LUNG INJURY

The adult respiratory distress syndrome is pulmonary edema with low heart pressures and hypoxemia. Based on experimental models of the human disease, it is likely that functional injury to the lung includes pulmonary vasoconstriction, a loss of hypoxic vasoconstriction, increases in resistance to airflow across the lungs, decreases in lung compliance (perhaps both resulting from airway constriction), and lung microvascular injury resulting in pulmonary edema. Data accumulated over the last several years strongly suggest an important role for both cyclo-oxygenase metabolites and lipoxygenase metabolites of arachidonic acid in mediating lung vascular injury in this syndrome. Likewise, more recent evidence suggests a causative role for granulocytes in mediating the lung injury. Based on what is known about the biological activity of products of granulocytes and metabolites of arachidonic acid, it is reasonable to hypothesize a sequence of events in which arachidonate metabolites and granulocytes interact to result in pulmonary vasoconstriction, loss of hypoxic vasoconstriction, airway responses and capillary injury. It remains possible, perhaps even likely, that other humoral mediators, platelets and perhaps even other cellular mediators (for example, mast cells or lymphocytes) participate in the pathogenic sequence of events in ARDS. Specific delineation of the mechanisms of lung injury in this syndrome must await further research.