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Humans↗
Biomedical subjects
W D Lucht
Publications and source records attributed to W D Lucht.
Corticosteroids inhibit endotoxin-induced lung lymph neutrophil stimulating activity in sheep.
The Adult Respiratory Distress Syndrome (ARDS) most frequently is the result of sepsis. Accumulation of neutrophils in lung interstitium is a well-documented phenomenon, but the nature of their presence remains obscure. We hypothesized that endotoxin causes the release of substances into lung lymph that activate neutrophils and that methylprednisolone may prevent sequestration and activation of neutrophils. We used the sheep lung lymph fistula-endotoxin model of ARDS to test this hypothesis. Unanesthetized animals were given either 0.5 microgram/kg of E. coli endotoxin intravenously alone or, on a different experimental day, an identical dose of endotoxin preceded by a 1 gm bolus of methylprednisolone plus a 1 gm/hr continuous infusion. Endotoxin infusion caused the release of substances into lung lymph that were capable of stimulating normal sheep neutrophils to aggregate, migrate, and release superoxide. This activity appeared within 1 hour of endotoxin and persisted for at least 4 hours. Pretreatment by methylprednisolone did not prevent the early activity but did significantly reduce such activity 3-4 hours after endotoxin, when the permeability defects caused by endotoxin are most pronounced. We speculate that endotoxin-stimulated production of humoral neutrophil-activating substances in the lung may play a role in the pathogenesis of acute lung injury.
Animals↗
Pulmonary function in long-term survivors of hyaline membrane disease.
In order to determine the long-term pulmonary consequences of hyaline membrane disease (HMD), we measured pulmonary function and airway responsiveness to methacholine in 22 survivors of HMD aged 18 to 22 years. Nineteen age-matched control subjects without a history of lung disease or asthma were also studied. There was no statistically significant difference between the mean pulmonary function test results of the control vs the HMD group. The mean N2 delta of the five HMD patients who required assisted ventilation was significantly different from that of the control group. Airway responsiveness to methacholine, as estimated by the dose of methacholine aerosol necessary to provoke a 35 percent fall in SGaw did not differ between the control and HMD groups. In the absence of prematurity, low birth weight (less than 1,500 g), and requirement for positive pressure ventilation, HMD is not associated with an increase in nonspecific airway reactivity or abnormal pulmonary function in adulthood.
Adolescent↗
Prevention of release of granulocyte aggregants into sheep lung lymph following endotoxemia by N-acetylcysteine.
Interactions of granulocytes with the lungs are altered by endotoxemia and may be critical in the pathogenesis of endotoxin-induced lung injury. In chronically instrumented unanesthetized sheep, we measured the ability of lung lymph to aggregate normal sheep neutrophils in vitro. We found a marked increase in lung lymph aggregating activity beginning within 1 hour after endotoxin infusion and persisting for several hours. When n-acetylcysteine was administered to the animals before endotoxin infusion, neutrophil aggregating activity in lung lymph after endotoxin infusion was markedly reduced. N-acetylcysteine did not affect neutrophil aggregation, adherence, or leukotriene B4 production in vitro and did not prevent complement activation at concentrations achieved in vivo. It is concluded that endotoxemia causes release from the lungs of substance(s) that activate granulocytes, and that this response is prevented by n-acetylcysteine, possibly as a result of the antioxidant properties of the drug.
Acetylcysteine↗
Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function.
Oxygen free radicals released during endotoxemia may contribute to the lung injury of the adult respiratory distress syndrome (ARDS). As this syndrome occurs frequently after gram-negative sepsis in humans, we studied the effect of intravenous N-acetylcysteine (NAC), a free radical scavenger, upon the endotoxin (E)-induced model of ARDS in awake sheep. In vivo studies demonstrated that NAC attenuates the endotoxin-induced rise in pulmonary artery pressure (62 +/- 3 torr with E control vs. 43 +/- 3 torr for E + NAC), and markedly diminishes the rise in lymph flow at 1 h (8.5 +/- 1.2 vs 4.5 +/- 0.6 ml/15 min) and 4 h (5.0 +/- 0.6 vs. 3.3 +/- 0.4 ml/15 min), respectively, for E control vs. E + NAC. NAC also markedly attenuated the alterations in lung mechanics after endotoxemia. Dynamic compliance at 2 h after endotoxemia was 44 +/- 6% of base line for E vs. 76 +/- 10% of base line for E + NAC. Resistance to airflow across the lung at 1 h postendotoxin was 811 +/- 280% of base line for E vs. 391 +/- 233% of base line for E + NAC. NAC substantially reduced the 1 h postendotoxin rise in lymph concentrations of thromboxane B2 (8.29 +/- 3.28 vs. 2.75 +/- 1.93 ng/ml for E vs. E + NAC) and 6-keto-prostaglandin-F1 alpha (0.91 +/- 0.27 vs. 0.23 +/- 0.12 ng/ml for E vs. E + NAC). In addition, in vitro studies were performed which revealed NAC to be a potent free radical scavenger in both biologic and nonbiologic free radical generating systems. NAC decreased phorbol-stimulated granulocyte aggregation in a concentration-dependent manner in vitro. Minimal effects were observed, however, upon leukocyte degranulation at the concentrations of NAC achieved during the in vivo tests. Thus, NAC significantly attenuated all monitored pathophysiologic changes in the endotoxin model of ARDS in sheep, possibly by its ability to scavenge toxic oxygen free radicals. A direct impairment of the ability of inflammatory cells to generate oxygen radicals cannot be ruled out.
Acetylcysteine↗
Septicemia and lung injury.
The results of investigations undertaken by the authors which deal with the functional and structural changes in the lungs resulting from gram-negative bacterial endotoxemia and the mechanisms of these changes are analyzed. The authors emphasize the major roles played by granulocytes and metabolites of arachidonic acid in mediating endotoxin-induced lung injury.
Adult↗