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G Feuerstein

Publications and source records attributed to G Feuerstein.

At least 19 recordsLinked to original sources
PubMed2000

An improved clinically relevant sepsis model in the conscious rat.

OBJECTIVE: To develop an improved small animal experimental paradigm that more closely mimics human sepsis. DESIGN: Prospective, randomized, controlled animal study. SETTING: Medical school research laboratory. SUBJECTS: Male Sprague-Dawley rats (280-320 g). INTERVENTIONS: We monitored the hemodynamic, hematologic, and biochemical consequences of abdominal sepsis produced by intraperitoneal implantation of a fibrin clot containing Escherichia coli in conscious, antibiotic-treated, rats. MEASUREMENTS AND MAIN RESULTS: Similar to human sepsis, the implanted, infected clot (LD50 = 5-7 x 10(8) colony forming units/mL, n = 6) elevated cardiac index (>7% vs. sterile clot, p < .05, at 4 hrs), whereas mean arterial pressure and heart rate remained unaffected. The total peripheral resistance index and stroke volume index tended to decrease and increase, respectively. In contrast, an intravenous bolus injection of endotoxin (LD50 of E. coli lipopolysaccharide = 5.6 mg/kg, n = 7), the most commonly used sepsis model, induced profound hypodynamic responses manifested by a 27% decrease (vs. endotoxin vehicle, p < .01) in cardiac index, a 28% increase in the total peripheral resistance index (p < .01), and a 33% decrease in the stroke volume index (P < .01). The infectious peritonitis model also displayed dose-dependent thrombocytopenia (<61%, p < .05), leukopenia (<60%, p < .05), and mortality rate (50% at 5-7 x 10(8) colony forming units/mL, p < .05) with a minimally elevated serum tumor necrosis factor-alpha level (145 vs. 12 +/- 6 pg/mL in controls, p < .05). CONCLUSION: This rodent model of antibiotic-treated, intra-abdominal infection features key characteristics of clinical sepsis. Although the hyperdynamic response observed in septic patients undergoing resuscitation was not clearly elicited, this paradigm better mimics clinical sepsis compared with the commonly used endotoxin model. Thus, utilization of this paradigm may provide additional opportunities to explore mechanisms of sepsis and to examine novel therapeutics.

Animals↗
PubMed1999

Vascular effects of lipopolysaccharide are enhanced in interleukin-10-deficient mice.

BACKGROUND AND PURPOSE: The role in blood vessels of interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is not known. Using mice with targeted deletion of the gene for IL-10 (IL-10(-/-)), we examined the hypothesis that IL-10 is a major modulator of the vascular effects of lipopolysaccharide (LPS). Methods-We examined in vitro responses of carotid arteries obtained from wild-type (129/SvEv or C57BL/6; IL-10(+/+)) and IL-10-deficient mice 6 hours after injection of a relatively low dose of LPS (10 microgram). RESULTS: Contraction of the carotid artery in response to U46619 was impaired in IL-10-deficient mice treated with LPS compared with LPS-treated controls. After LPS, U46619 (0.03 and 0.1 microgram/mL) contracted the carotid artery by 0.11+/-0.02 (mean+/-SEM) and 0.38+/-0.03 g in wild-type (n=10) and 0.03+/-0.01 and 0.19+/-0.03 g in IL-10-deficient (n=8) mice (P<0.05 versus control). Aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), had no significant effect on contraction of the carotid artery from LPS-treated control mice but restored contraction of the carotid artery in response to U46619 in IL-10-deficient mice to levels seen in wild-type mice. Similar findings were obtained when phenylephrine was used as a vasoconstricting agent. These findings indicate that LPS produces much greater impairment of contractile responses of the carotid artery in IL-10-deficient mice than in control mice. Impaired contractile function was eliminated by aminoguanidine, suggesting that expression of iNOS is enhanced in arteries from IL-10-deficient mice. In carotid arteries from animals injected with LPS, reverse transcription-polymerase chain reaction (RT-PCR) products for iNOS were found more frequently in IL-10-deficient mice than in wild-type mice. RT-PCR products for iNOS were not present in arteries from vehicle-treated animals (IL-10-deficient or wild-type mice). CONCLUSIONS: This is the first evidence that endogenous IL-10 is a major determinant of the effects of LPS on vascular tone. The results suggest that impaired constrictor responses of the carotid artery after LPS in IL-10-deficient mice are mediated by enhanced expression of iNOS.

Animals↗
PubMed1998

Neuroprotective activities of carvedilol and a hydroxylated derivative: role of membrane biophysical interactions.

Carvedilol is a vasodilating beta-blocker and antioxidant approved for treatment of mild to moderate hypertension, angina, and congestive heart failure. SB 211475 (4-[2-hydroxyl-3-[[2-(2-methoxyphenoxy)ethyl]amino]propoxyl]-9H-++ +carbazol-3-ol), a hydroxylated carvedilol analogue, is an even more potent antioxidant in several assay systems. Carvedilol also has neuroprotective capacity with modulatory actions at N-methyl-D-aspartate (NMDA) receptors and Na+ channels. In the present study, we demonstrated that in cultured rat cerebellar neurons, SB 211475 has 28-fold greater antioxidant activity than carvedilol, but is 2- to 6-fold less potent, respectively, at inhibiting neurotoxic activities at Na+ channels and at NMDA receptor channels. To determine a biophysical rationale for these differential activities, small angle x-ray scattering data were obtained from model lipid and brain membrane bilayers containing either carvedilol, SB 211475, or dihydropyridine calcium channel blockers. Electron density profiles revealed that the location of SB 211475 was restricted to the glycerol backbone/hydrocarbon interface and significantly reduced membrane width by 5%, whereas the time-averaged location for carvedilol and flunarizine also extended to the hydrated surface of the bilayer. Comparison of carvedilol with several dihydropyridines showed a correlation between high ClogP values (lipophilicity), Na+ channel inhibitory potency, and bilayer localization. The antioxidant activity of SB 211475 could be explained by restricted intercalation into the glycerol phosphate/hydrocarbon interface, creating an increase in volume associated with the phospholipid acyl chains, which would then become resistant to lipid peroxidation. Differential channel modulation may also be explained by these membrane structural results, which indicate that carvedilol and the less spatially restricted dihydropyridine molecules are more likely to inhibit transmembrane receptor channels.

Animals↗
PubMed1998

Comparison of metoprolol and carvedilol pharmacology and cardioprotection in rabbit ischemia and reperfusion model.

Carvedilol, a selective alpha1 and non-selective beta-adrenoceptor antagonist and antioxidant, has been shown to provide significant cardiac protection in animal models of myocardial ischemia. To further explore the mechanisms contributing to carvedilol cardioprotection efficacy, the effects of carvedilol on hemodynamic variables, infarct size and myeloperoxidase activity (an index of neutrophil accumulation) were compared with a beta1-selective adrenoceptor antagonist, metoprolol. Carvedilol (1 mg/kg) or metoprolol (1 mg/kg or 1 mg/kg + 0.5 mg/kg 90 min later) was given intravenously 5 min before reperfusion. In vehicle-treated rabbits, ischemia (60 min) and reperfusion (180 min) resulted in significant increments in left ventricular end diastolic pressure, large infarcts (59+/-2.6% of area-at-risk) and marked increase in myeloperoxidase activity (0.59+/-0.09 U/100 mg tissue). Carvedilol treatment resulted in sustained reduction of pressure-rate-index and significantly smaller infarcts (22.0+/-2.5%, P < 0.01 vs. vehicle) as well as decreased myeloperoxidase activity (0.186+/-0.056 U/100 mg tissue, P < 0.01 vs. vehicle). The highest dose of metoprolol, 1 mg/kg + 0.5 mg/kg, that resulted in pressure-rate-index comparable to that of 1.0 mg/kg carvedilol, failed to reduce myeloperoxidase activity in the ischemic myocardial tissue, and the infarct size (35+/-3.1%) was significantly larger than in carvedilol-treated animals. Taken together, this study suggests that the superior cardioprotection of carvedilol over metoprolol is not a consequence of hemodynamic variances but possibly the result of the additional pharmacological properties of carvedilol such as the antioxidant and anti-neutrophil effects.

Adrenergic alpha-Antagonists↗
PubMed1998

Cytokines in brain ischemia--the role of TNF alpha.

1. The role of cytokines and other inflammatory mediators in the progression of ischemic brain injury is a new and exciting era of research. Evidence in support for a role for TNF alpha in this respect is emerging as evidence on de novo upregulation of TNF alpha following ischemia is now well established. 2. TNF alpha administered directly to the brain parenchyma elicits local microvascular injury in the form of pericapillary edema and leukocyte adhesion to cerebral capillaries. 3. TNF alpha administered into the cerebroventricular space prior to ischemia augment the extent of tissue damage and neurological deficits. 4. Specific and potent inhibitors of TNF alpha synthesis or TNF alpha receptors must be developed and tried to prove firmly a role for TNF alpha in ischemic brain injury.

Animals↗
PubMed1998

Effects of the novel antimigraine agent, frovatriptan, on coronary and cardiac function in dogs.

The effects of frovatriptan (VML 251/SB-209509) on coronary artery function were investigated in isolated coronary arteries from beagle dogs. Low concentrations of frovatriptan produced contraction with -logEC50 7.55 +/- 0.08 (n = 11). The maximal observed contraction attained was 56 +/- 7% of the control 5-hydroxytryptamine (5-HT; 10 microM) response. At high concentrations of frovatriptan (>6 microM), reversal of sumatriptan (10 microM)-induced contractions was noted. In arteries precontracted with the thromboxane mimetic, U46619, frovatriptan produced a bell-shaped concentration-response relation with a maximal response at 600 nM. Concentrations of frovatriptan >2 microM produced marked reversal of tone, with full relaxation of precontracted tissues at 200 microM. In anesthetized, open-chest mongrel dogs, intravenous (n = 5) or intracoronary (n = 5) artery administration of frovatriptan (0.0001-1 mg/kg) had no consistent effect on left ventricular end-diastolic pressure, left end-systolic pressure, cardiac contractility, aortic blood flow, systemic peripheral resistance, coronary blood flow, coronary vascular resistance, mean arterial blood pressure, or heart rate when compared with vehicle (n = 3). Intravenous sumatriptan produced minor effects on blood pressure and heart rate. Intracoronary artery administration of sumatriptan (0.0003 mg/kg) produced an increase in systemic peripheral resistance to 120.5 +/- 8.2% compared with vehicle (97.8 +/- 5.4%; p < 0.05). This dose of sumatriptan also produced a significant increase in coronary blood flow and decrease in coronary vascular resistance. Intravenous administration of sumatriptan produced a dose-related reduction in left ventricular diastolic pressure with a reduction to 58.3 +/- 8.3% and 41.7 +/- 25% of control values observed at 0.3 and 1 mg/kg, respectively; however, administration of sumatriptan by an intracoronary route had no effect. In a model of myocardial infarction, comparable doses of sumatriptan (1.0 mg/kg) or frovatriptan (0.1 mg/kg), in terms of their effect on carotid vascular resistance, had no significant effect on infarct size. Frovatriptan had no effect on coronary blood flow after reperfusion; however, sumatriptan produced a significant reduction in coronary blood flow for < or =3 h. These studies show that frovatriptan has the capability of relaxing coronary arteries in vitro, has no overall effect on cardiac function at rest with no effect on coronary hemodynamics after myocardial infarction, and has a profile superior to that of sumatriptan.

Animals↗
PubMed1998

Effect of liposome-encapsulated hemoglobin on the development of endotoxin-induced shock in the rat.

Liposome-encapsulated hemoglobin (LEH) is an experimental oxygen-carrying resuscitation fluid. Because LEH is cleared from the circulation primarily by the reticuloendothelial system, its effect on the development of sepsis remains a major concern. Thus, the present study aimed to evaluate whether LEH modifies consequences of endotoxemia in the conscious normovolemic rat. LEH infusion at 10% of estimated blood volume (n = 10) did not affect mortality (30%, p < .05) and serum tumor necrosis factor-alpha levels (6204 +/- 414, p < .05) induced by 3.6 mg/kg Escherichia coli endotoxin administered (intravenous bolus) 22 h later. In contrast, when a shorter LEH-endotoxin time interval (<12 h, n = 10) or a higher dose of endotoxin (14.4 mg/kg, n = 20) was tested, LEH enhanced endotoxin-induced mortality (90% and 100%, respectively, p < .05) and broadened serum tumor necrosis factor-alpha response without modifying its peak levels. LEH (n = 20) did not exacerbate the endotoxin-induced tachycardia, leukopenia, and thrombocytopenia. Therefore, in this model, the effect of LEH on endotoxin-induced responses was dependent on the time interval between LEH and endotoxin administration as well as the endotoxin dose. The clinical relevance of these results should be further investigated.

Animals↗
PubMed1997

The novel chemokine mob-1: involvement in adult respiratory distress syndrome.

BACKGROUND: Using differential display reverse transcriptase-polymerase chain reaction we have recently identified mob-1, the novel rat homologue of the human alpha-chemokine IP-10, as a highly inducible gene in adult respiratory distress syndrome (ARDS) lungs. The present study aimed to further implicate mob-1 in the pathogenesis of ARDS. METHODS: Pulmonary mob-1 mRNA up-regulation was confirmed by Northern blot analysis in three different rat models of ARDS-like lung injury and localized to pulmonary macrophages by using in situ hybridization. Also, Escherichia coli-derived recombinant mob-1 (rmob-1) was tested for its properties in relationship to lung injury. RESULTS: In vivo, intratracheal injection of rmob-1 (50 micrograms/rat) induced pulmonary leukosequestration (myeloperoxidase +93% +/- 8% versus control, p < 0.05) with preferential accumulation of neutrophils in bronchoalveolar lavage fluid (36.0% +/- 1.0% versus 0.1% +/- 0.1% in controls, p < 0.01). In vitro, transwell migration studies demonstrated chemotactic activity of rmob-1 (50 to 100 ng/ml) toward human monocytes (+151% +/- 34% versus rmob-1 vehicle, p < 0.01) and only weak chemotaxis for human neutrophils (+15% +/- 0% versus rmob-1 vehicle, p < 0.01). Utilizing a rat aortic ring model ex vivo, rmob-1 at 100 ng/ml exerted a very potent inhibitory effect on angiogenesis (-78.7% +/- 6.3% versus rmob-1 vehicle, p < 0.01), a major component of the resolution phase of ARDS. CONCLUSIONS: Taken together, these data support the involvement of mob-1 in the pathogenic mechanisms of ARDS possibly through chemotaclic actions on inflammatory cells and modulation of angiogenesis in the recovery phase of the disease.

Animals↗
PubMed1997

Platelet-activating factor and cardiac diseases: therapeutic potential for PAF inhibitors.

Platelet-activating factor (PAF) is a potent phospholipid mediator released from inflammatory cells in response to diverse immunologic and non-immunologic stimuli. Animal studies have implicated PAF as a major mediator involved in coronary artery constriction, modulation of myocardial contractility and the generation of arrhythmias which may bear on cardiac disorders such as ischemia, infarction and sudden cardiac death. PAF effects are induced by direct actions of PAF on cardiac tissue to modify chronotropic and inotropic activity, or indirectly via the release of eicosanoids such as thromboxane A2 (TXA2), leukotrienes (LT) or cytokines (TNF alpha). The development of selective, high affinity PAF receptor antagonists has permitted investigations on the role of PAF in experimental animal models of cardiac injury. In vivo and in vitro studies strongly suggest that PAF receptor antagonists might convey therapeutic benefits in ischemic conditions and certain arrhythmias. In addition, PAF antagonists might have a cardiac allograft-preservation effect. Although clinical studies with PAF receptor antagonists in patients with cardiac diseases have not yet been reported, the experimental results to date suggest that PAF receptor antagonists might be useful in some specific cardiac disorders in humans.

Animals↗
PubMed1997

Liposome encapsulation attenuates hemoglobin-induced vasoconstriction in rabbit arterial segments.

Free hemoglobin (Hb) induces a potent vasoconstrictor response that may limit its therapeutic application as a red blood cell replacement. We have investigated whether encapsulation of stroma-free Hb (SFHb) or cross-linked Hb (alpha alpha-Hb) in liposomes modulates Hb vasoactivity in isolated blood vessels. Relaxation of rabbit thoracic vessels was measured before and after exposure to acellular SFHb, alpha alpha-Hb, and liposome-encapsulated SFHb or alpha alpha-Hb. SFHb and alpha alpha-Hb caused significant inhibition of carbachol-induced relaxation at 0.5 mg/dl, whereas encapsulation inhibited vessel relaxation at 30- to 60-fold higher Hb concentrations. The contractile response of rabbit ear arterial segments to electrical stimulation in the presence of acellular alpha alpha-Hb resulted in a 150% increase (EC150) in contractile amplitude at 0.23 mg/dl, whereas the EC150 for encapsulated alpha alpha-Hb was 13.7 mg/dl. Mechanistic studies of the vasoconstrictor activity of Hb demonstrated that acellular alpha alpha-Hb had no effect on norepinephrine release in the rabbit ear artery. In addition, neither acellular nor encapsulated alpha alpha-Hb preparations inhibited endothelial nitric oxide (NO) synthase activity isolated from bovine pulmonary artery. However, inhibition of vessel relaxation by acellular or encapsulated alpha alpha-Hb was reversed by the NO donor S-nitrosylpenacillamine, implicating Hb-NO binding as a possible mechanism for the vasoconstrictor response. In vitro stopped-flow kinetic studies of Hb-NO binding showed similar rates of reaction for conversion of oxyhemoglobin to methemoglobin (metHb; < 2 ms), followed by rapid conversion of metHb to NO-Hb (300 ms) for both acellular and encapsulated alpha alpha-Hb, demonstrating that liposome encapsulation does not retard NO-Hb binding. The attenuated vasoactivity of encapsulated Hb may, therefore, result from the limited access of encapsulated Hb to NO imposed by the physical size of the liposome and reduced penetration of Hb across the vascular endothelium.

Animals↗
PubMed1996

Proteolytic cascade enzymes increase in focal cerebral ischemia in rat.

Cerebral infarction initiates a cascade of molecular events, leading to proteolytic cell death. Matrix-degrading metalloproteinases (MMPs) are neutral proteases involved in extracellular matrix damage. Type IV collagenase is an MMP that increases cerebral capillary permeability after intracerebral injection and may be important along with plasminogen activators (PA) in secondary brain edema in stroke. Therefore, we measured MMPs and PAs in spontaneously hypertensive (SHR) or Wistar-Kyoto (WKY) rats with permanent middle cerebral artery occlusion (MCAO). Brain tissue was assayed for MMPs and PAs at 1, 3, 12, and 24 h and 5 days after occlusion, using substrate gel polyacrylamide electrophoresis (zymography). SHR showed an increase in 92-kDa type IV collagenase (gelatinase B) in the infarcted hemisphere compared with the opposite side at 12 and 24 h (p < 0.05). Gelatinase A remained the same in both infarcted and normal tissue until 5 days after injury, when it increased significantly (p < 0.05). Urokinase-type PA was increased significantly at 12 and 24 h and 5 days, while tissue-type PA was decreased significantly at 1, 12, and 24 h in the ischemic compared with the nonischemic hemisphere. Gelatinase B was markedly increased in SHR at 12 and 24 h compared with WKY (p < 0.05). Secondary vasogenic edema is maximal 1-2 days after a stroke, which is the time that gelatinase B was elevated. The time of appearance of gelatinase B suggests a role in secondary tissue damage and vasogenic edema, while gelatinase A may be involved in tissue repair.

Animals↗
PubMed1996

Evidence for activation of endothelium and monocytes in hypertensive rats.

We have proposed that an interaction between perivascular macrophages and endothelium via cytokines could underlie the increased risk of stroke in hypertension. Therefore, the activation of monocytes, the endothelial expression of intercellular adhesion molecule-1 (ICAM-1), and the numbers of monocytes/macrophages in carotid arteries, as well as the cytokine production in carotid tissue, of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto and Sprague-Dawley rats were studied. The total number of blood monocytes (890 +/- 153 cells/mm3, n = 10) and the number of activated (nitro blue tetrazolium-positive) monocytes (220 +/- 51 cells/mm3, n = 10) were significantly greater (P < 0.05) in SHR than in WKY rats (440 +/- 81 and 40 +/- 16 cells/mm3, respectively, n = 10). Patchy endothelial expression of ICAM-1 was found in 77 +/- 9% of carotid sections from stroke-prone SHR (SHR-SP, n = 5) and in 75 +/- 7% of the sections from SHR (n = 7) but in none of the sections from the two normotensive rat strains (n = 7). The number of endothelium-attached monocytes/macrophages per millimeter of internal elastic lamina was significantly greater in SHR-SP than in SHR [5.1 +/- 0.7 (n = 4) and 3.3 +/- 0.3 (n = 6), P < 0.05], whereas no monocytes were found around the endothelium in either of the normotensive rat strains (n = 7 in each group). Incubation of the carotid arteries with lipopolysaccharide (30-300 ng/ml) induced a concentration-dependent expression of mRNAs for interleukin-1 beta and release of tumor necrosis factor-alpha to a significantly greater degree in the SHR than in the Wistar-Kyoto rats. The results demonstrate that hypertension is associated with activation of monocytes and endothelium and an increased endothelial adhesion and subendothelial accumulation of monocytes/macrophages and with an increased vascular capacity to produce cytokines.

Animals↗
PubMed1996

Locally produced tumor necrosis factor-alpha mediates interleukin-2-induced lung injury.

Interleukin (IL)-2-induced microvascular lung injury is an experimental paradigm commonly used to investigate the pathogenesis of the adult respiratory distress syndrome. Since tumor necrosis factor-alpha (TNF-alpha) is known to induce such an injury in vivo and since TNF-alpha is involved in other models of lung injury, we postulated that it might also mediate pulmonary toxicity after IL-2 administration. The present study tested this hypothesis by evaluating the effect of TNF-alpha inhibition on IL-2-induced lung injury in the rat. Recombinant human IL-2 (10(6) U IV per rat, n = 6) elevated lung water, myeloperoxidase activity, and protein accumulation in bronchoalveolar lavage fluid and induced tissue hypoxia. Also, IL-2 enhanced lung tissue TNF-alpha mRNA and peptide (1543 +/- 496 pg/g lung wet weight) localized to alveolar macrophages by in situ hybridization. In marked contrast, IL-2 failed to affect serum TNF-alpha, which remained at undetectable levels. Pretreatment with anti-TNF-alpha monoclonal antibody (25 mg/kg IV, n = 7) or the TNF-alpha synthesis inhibitor rolipram (200 micrograms/kg IV, n = 7) attenuated lung injury and reverted tissue hypoxia. Furthermore, TNF-alpha inhibition prevented the upregulation of lung tissue IL-1 beta, IL-6, cytokine-induced neutrophil chemoattractant, and E-selectin (ELAM-1) but not intercellular adhesion molecule-1 mRNAs in response to IL-2. These data imply that locally produced TNF-alpha mediates IL-2-induced lung inflammation and tissue injury and point to the potential utilization of TNF-alpha inhibitors in treating the pulmonary toxicity of IL-2 immunotherapy.

Animals↗
PubMed1995

Binding of the nonpeptide antagonist, SB 209670, to endothelin receptors on cultured neurons.

We studied the binding characteristics of a novel, nonpeptide endothelin antagonist, SB 209670, to two subtypes of endothelin (ET) receptor in cultured rat cerebellar granule cell neurons. Displacement binding studies of [125I]ET-1 performed in the presence of the ETB receptor-selective agonist, sarafotoxin 6c (S6c), allowed us to measure a Ki of 4.0 +/- 1.5 nM for (+/-)SB 209670 at the ETA receptor (n = 4). Similarly, binding studies in the presence of the ETA receptor-selective antagonist, BQ123, allowed us to measure a Ki of 46 +/- 14 nM for (+/-)SB 209670 at the ETB receptor (n = 4). These studies indicate that the novel endothelin antagonist, SB 209670, has high affinity for both types of neuronal endothelin receptor.

Animals↗
PubMed1995

Aspiration-induced lung injury: role of complement.

OBJECTIVES: To examine the role of complement in the development of acid aspiration-induced lung injury in the rat. It was postulated that inhibition or depletion of complement attenuates aspiration-induced lung injury. DESIGN: Controlled animal trial. SETTING: Animal Laboratory, Jefferson Medical College, Philadelphia, PA. SUBJECTS: Anesthetized rats. INTERVENTIONS: Aspiration was induced by the intratracheal administration of 0.2 mL of 0.1 N hydrochloric acid (n = 7) and lung injury was evaluated by determining water content, myeloperoxidase activity, protein concentration, and leukocyte count in bronchoalveolar lavage fluid. Muscle PO2 was directly measured using a thin-film chamber oxygen sensor and serum tumor necrosis factor-alpha was assayed by enzyme-linked immunosorbent assay. The effect of complement inhibition by recombinant human soluble complement receptor type 1 (n = 8) or complement depletion by cobra venom factor (n = 7) on lung injury was evaluated. MEASUREMENTS AND MAIN RESULTS: Acid aspiration induced pulmonary leukosequestration, edema, and a microvascular permeability defect, along with tissue hypoxia. Pretreatment with soluble complement receptor type 1 (complement inhibition) or cobra venom factor (complement depletion) significantly reduced lung edema (-61 +/- 7%; p < .05), eliminated protein accumulation in bronchoalveolar lavage fluid (p < .01), and improved (p < .05) tissue oxygenation. In contrast, there was no effect of soluble complement receptor type 1 or of cobra venom factor on leukosequestration. CONCLUSIONS: Acid aspiration induces lung injury through a complement-dependent mechanism that leads to microvascular permeability defects. Therefore, the possibility that complement inhibitors may have a salutary effect in humans with aspiration-induced lung injury should be investigated.

Animals↗