Biomedical subjects

C H Welsh

Publications and source records attributed to C H Welsh.

23 records · Page 2Linked to original sources

PubMed1989

Endotoxin-pretreated neutrophils increase pulmonary vascular permeability in dogs.

Endotoxin causes pulmonary vascular neutrophil sequestration and injures the lung. Whether this is primarily due to a direct effect of endotoxin on the endothelium or is mediated by an action on the neutrophil is unclear. Canine neutrophils, isolated on plasma-Percoll gradients in vitro, were incubated with Salmonella enteriditis endotoxin, washed, and injected via wedged pulmonary arterial catheters into discrete lung zones of anesthetized dogs, whereas untreated neutrophils were administered into contralateral control lung zones. 113mIn-transferrin was administered intravenously 2 h before the animals were killed. Morphometry and extravascular protein accumulation were assessed at 4 h. Endotoxin treatment of neutrophils ex vivo induced a two- to three-fold increase in neutrophils in these lung zones (0.096 +/- 0.012 vs. 0.05 +/- 0.002 neutrophils/alveolar septal intercept, P less than 0.05). Extravascular-to-intravascular protein ratios in zones receiving endotoxin-treated neutrophils were significantly increased compared with control zones (0.146 +/- 0.02 vs. 0.079 +/- 0.02, P less than 0.05). Because complement fragments increase injury to endothelium in vitro, exogenous C5 fragments were administered to other dogs before administration of neutrophils but failed to significantly increase the extravascular protein signal (0.154 +/- 0.03 vs. 0.124 +/- 0.04). In summary, endotoxin treatment of neutrophils leads to neutrophil sequestration and increased pulmonary extravascular protein accumulation. C5 fragments failed to further enhance the protein accumulation. These data are consistent with an effect of endotoxin on the neutrophil to initiate neutrophil-endothelial interaction and subsequent lung injury.

Animals↗

PubMed1988

Pentoxifylline decreases endotoxin-induced pulmonary neutrophil sequestration and extravascular protein accumulation in the dog.

Since neutrophils may be important in endotoxin-induced acute lung injury, we sought to determine whether injury produced by endotoxin in vivo would be modified by pentoxifylline, which decreases neutrophil adherence and lessens neutrophil activation in vitro. Anesthetized dogs received 4 micrograms/kg Salmonella enteriditis endotoxin intravenously after pretreatment with either saline or pentoxifylline 20 mg/kg intravenously administered followed by a continuous 0.1 mg/kg/min infusion. Two hours after endotoxin, pulmonary vascular permeability to protein was assessed as the lung extravascular accumulation of intravenously administered 113mIn-transferrin. Results expressed as the ratio of extra- to intravascular protein activities showed a clear increase over control values in dogs treated with endotoxin [0.064 +/- 0.003 (mean +/- SEM) and 0.31 +/- 0.14 respectively, p less than 0.05]. This increase with endotoxin was reversed by pentoxifylline to levels similar to control values (0.063 +/- 0.044, p less than 0.05). To determine whether pentoxifylline influenced neutrophil sequestration, thin sections of lung tissue were analyzed for neutrophil density using an intercept counting technique. Neutrophil density was doubled in dogs treated with endotoxin over that seen in controls (0.078 +/- 0.008 versus 0.042 +/- 0.006 neutrophils per alveolar septa, respectively, p less than 0.05) and this increase was significantly reduced by pentoxifylline treatment (0.048 +/- 0.009, p less than 0.05). Endotoxin increased lung retention of radiolabeled neutrophils and this was also prevented by pretreatment of the neutrophils with pentoxifylline. In summary, pentoxifylline decreases neutrophil accumulation and prevents the increase in pulmonary vascular permeability to protein induced by endotoxin. These data support the premise that pentoxifylline is protective against endotoxin-induced lung injury in vivo.

Animals↗

PubMed1987

Antiarrhythmic agents diminish thiourea-induced pulmonary vascular protein leak in rats.

Drugs possessing membrane stabilizing activity might act to diminish the augmented microvascular permeability resulting from acute lung injury. To test this rats were pretreated with quinidine, procainamide, or lidocaine and then given the lung injury-inducing agent thiourea. Vascular permeability, assessed as the extravascular accumulation of radiolabeled protein, was increased more than threefold by thiourea. This increase was diminished by 29, 34, and 43% after pretreatment with procainamide, quinidine, and lidocaine, respectively. Lidocaine also returned the thiourea-induced increase in lung wet weight-to-dry weight ratios to control levels. This protection was not likely due to hemodynamic effects of these agents, since no differences were noted in cardiac output between pretreated rats and those receiving thiourea alone and a small increase in mean pulmonary arterial pressure in the lidocaine-pretreatment group was the only difference noted. O2 metabolites have been implicated in the pathogenesis of thiourea-induced lung injury. None of these agents scavenged O2- or H2O2 directly, but quinidine and procainamide diminished in vitro neutrophil O2- and H2O2 production, and lidocaine inhibited neutrophil H2O2 production. However, neutropenia (PMN less than 100/ml) induced with either vinblastine or cyclophosphamide (Cytoxan) failed to prevent thiourea-induced increases in pulmonary vascular protein leak. In conclusion, procainamide, quinidine, and lidocaine diminished lung injury in rats after thiourea. Although these agents diminish PMN O2 metabolite production in vitro their salutary role in thiourea-induced lung injury appears to be through an unknown mechanism that is independent of their effects on neutrophil O2 metabolite-dependent toxicity.

Animals↗

PubMed1986

Endotoxin increases pulmonary vascular protein permeability in the dog.

Endotoxin increases pulmonary vascular permeability consistently in some species but fails to reliably cause injury in the dog. We wondered whether this phenomenon depended on the method of injury assessment, as others have relied on edema measurement; we quantified injury by monitoring the rate of extravascular protein accumulation. 113mIn-labeled protein and 99mTc-labeled erythrocytes were injected into anesthetized dogs and monitored by an externally placed lung probe. A protein leak index, the rate of extravascular protein accumulation, was derived from the rate of increase in lung protein counts corrected for changes in intravascular protein activity. After administration of Salmonella enteriditis endotoxin (4 micrograms/kg), the protein leak index was elevated 2.5-fold (41.1 +/- 4.6 X 10(-4) min-1) compared with control (16.0 +/- 2.8 X 10(-4) min-1). In contrast, wet-to-dry weight ratios failed to increase after endotoxin (4.6 +/- 0.8 vs. control values of 4.2 +/- 0.5 g/g dry bloodless lung). However, we observed that endotoxin increased lung dry weight (per unit body weight), which may have attenuated the change in wet-to-dry weight ratios. To determine whether low microvascular pressures following endotoxin attenuated edema formation, we increased pulmonary arterial wedge pressures in five dogs by saline infusion, which caused an increase in wet-to-dry weight ratios following endotoxin but no change in the five controls. We conclude that low dose endotoxin causes pulmonary vascular protein leak in the dog while edema formation is minimal or absent.

Animals↗

PubMed1985

Cigarette smoking and health.

Cigarette smoking is the major preventable cause of increased mortality and premature disability in the United States. Smoking is a proven cause of coronary heart disease, chronic bronchitis and emphysema, and lung and other cancers. Maternal smoking is associated with low infant birth weight, increased perinatal mortality, and several complications of pregnancy. Passive smoking is associated with increased incidence of lower respiratory tract infections in very young children and may increase the risk of lung cancer in the nonsmoker. Smoking cessation is difficult because of nicotine addiction and psychological and social factors. Physicians and other health professions must be active both in helping people quit smoking and in preventing nonsmokers from starting. We recommend a national effort focused on preventing young people from starting to smoke.

Cardiovascular Diseases↗