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H B Hechtman

Publications and source records attributed to H B Hechtman.

At least 55 records · Page 3Linked to original sources
PubMed1996

Complement inhibition by soluble complement receptor type 1 fails to moderate cerulein-induced pancreatitis in the rat.

CONCLUSION: Cerulein-induced pancreatitis in rats associated with remote liver and lung dysfunction. Soluble complement receptor 1 (sCR1) does not reduce the local or remote injury. Thus complement activation does not moderate cerulein-induced pancreatitis or the associated liver and injury. BACKGROUND: The local and remote injury of pancreatitis resembles other inflammatory events that are mediated by complement. This study examines the effect of complement inhibition with sCR1 in cerulein-induced pancreatitis in rats. METHODS: Thirteen Sprague-Dawley rats received five hourly subcutaneous doses of cerulein (100 micrograms initially, then 50 micrograms/kg). Six of these animals received hourly i.v. sCR1 (15 mg/kg, a proven complement-inhibiting dose in rats) and the other seven received i.v. saline. In parallel, 12 additional rats received hourly s.c. and i.v. saline. RESULTS: Compared to saline controls, rats receiving cerulein showed increased pancreatic wet-to-dry ratio (3.25:8.52), hematocrit (40 to 47%), ascites volume (2.1 to 6.1 mL), serum amylase (1680 to 10,700 U/L), and ascites amylase (32,200 to 167,000 U/L) (all p < 0.05). None of these parameters were modified by treatment with sCR1. Serum SGPT, which increased from 33.4 to 46.6 U/L in cerulein-infused rats, showed a trend toward reduction to 38.8 U/L in rats treated with sCR1. Cerulein-treated rats also had increased lung myeloperoxidase (0.069 to 0.097 U/g) and lung permeability, as assessed by a alveolar lavage to serum ratio of labeled albumen (0.041:0.121) both p < 0.05). Neither were changed by sCR1 treatment.

Acute Disease↗
PubMed1996

P-selectin mediates intestinal ischemic injury by enhancing complement deposition.

BACKGROUND: Ischemia and reperfusion injury of rodent intestine is complement mediated. P-selectin antagonism reduces local injury, yet neutrophil depletion does not. This study tests the thesis that the protective mechanism of P-selectin antagonists involves complement inhibition. METHODS: We subjected rats (n = 86) to 50 minutes of complete mesenteric ischemia and 4 hours of reperfusion. Treatment with a monoclonal antibody (PB1.3) against P-selectin reduced intestinal injury as judged by 125I-albumin permeability index (7.33 +/- 0.40) compared with saline solution treatment (11.4 +/- 0.49) (p < 0.05). RESULTS: However, intestinal neutrophil sequestration assessed by myeloperoxidase assay was unchanged. Immunohistochemistry revealed that mucosal C5b-9 was deposited in animals treated with saline solution and was absent in the sham group. PB1.3 treatment reduced C5b-9 deposition in the intestinal mucosa compared with that in animals treated with saline solution (p < 0.05). Neutrophil-dependent remote lung injury assessed by 125I-albumin permeability and pulmonary myeloperoxidase assay were not significantly reduced by PB1.3. Treatment with a soluble form of P-selectin ligand, sialyl Lewisx (sLex), reduced intestinal myeloperoxidase (0.065 +/- 0.006) compared with saline solution treatment (0.136 +/- 0.02) (p < 0.05), but it did not reduce permeability. Remote lung permeability was reduced (4.52 +/- 0.65 x 10(-3)) by sLex compared with saline solution treatment (6.11 +/- 0.41 x 10(-3)) (p < 0.05). CONCLUSIONS: Antagonizing the lectin domain of P-selectin and thereby neutrophil adhesion was without local benefit in this model. In contrast, PB1.3 exerted a novel antagonism of P-selectin and reduced complement deposition.

Animals↗
PubMed1996

Anti-selectin therapy modifies skeletal muscle ischemia and reperfusion injury.

Restoration of blood flow to ischemic skeletal muscle results in a reperfusion injury characterized by permeability edema in part mediated by neutrophils that adhere via the selectin family of adhesion molecules. Rats underwent 4 h of hindlimb tourniquet ischemia followed by 4 h reperfusion. The role of neutrophils was determined by rendering one group of animals neutropenic before ischemia. In additional experimental groups, selectins were blocked with either a soluble form of the selectin counter-receptor, sialyl-Lewis X (SLX) or a monoclonal antibody directed against P-selectin (PB1.3). Neutrophil depletion resulted in a 36.1% reduction in hindlimb permeability (p < .05). SLX reduced hindlimb permeability index (PI) 23.9% at 1 mg/kg and 36.1% at 10 mg/kg compared to a nonfucosylated oligosaccharide, sialyl-N-acetylactosamine (p < .05). SLX also reduced neutrophil sequestration by 48.6% (p < .05). PB1.3 reduced hindlimb injury by 26.5% (p < .05) but did not reduce leukosequestration. We interpret these data to indicate that ischemia and reperfusion lead to selectin-mediated neutrophil sequestration. The oligosaccharide SLX, while moderately effective in limiting neutrophil sequestration was as effective as neutrophil depletion in reducing hindlimb permeability. The lack of concordance between the ability of SLX and PB1.3 in limiting neutrophil sequestration and permeability indicate mechanisms of action of these two agents that are in addition to the blocking of adhesion.

Animals↗
PubMed1995

Neutrophil adhesion receptor CD18 mediates remote but not localized acid aspiration injury.

BACKGROUND: Acid aspiration leads to lung polymorphonuclear neutrophil (PMN) sequestration and an associated increase in permeability. Although it is known that the neutrophil adhesion receptor (CD18) plays no role in determining PMN accumulations in the region aspirated, we postulated that this PMN adhesion receptor and its endothelial ligand, intercellular adhesion molecule-1 (ICAM-1), mediate remote neutrophil sequestration. METHODS: Anesthetized rabbits underwent localized aspiration of either 0.1N HCl 0.1 ml/kg (n = 18) or saline solution (n = 18). RESULTS: After 30 minutes leukopenia was noted, 2290 +/- 200 white blood cells/mm3 (p < 0.05). At 3 hours diapedesis occurred in the aspirated segment with accumulations in bronchoalveolar lavage fluid (X10(4)) of 87 +/- 6 PMN/ml versus control of 6 +/- 1 PMN/ml (p < 0.05). Histologic evidence of generalized lung leukosequestration occurred. The wet to dry weight ratio of the nonaspirated lung rose to 5.7 +/- 0.2 versus control of 3.9 +/- 0.1 (p < 0.05). Treatment (n = 18) with the CD18 monoclonal antibody (mAb) (R15.7, 1 mg/kg) had no effect on neutrophil accumulations in the aspirated segment. However, the mAb attenuated the remote inflammatory response: early leukopenia (5790 +/- 400 white blood cells/mm3); lung leukosequestration (24 +/- 4 PMN/10 high-power fields); protein leak in bronchoalveolar lavage fluid (570 +/- 50 micrograms/ml); and edema, wet to dry weight ratio (4.9 +/- 0.1) (all p < 0.05). Treatment with the ICAM-1 mAb (RR1/1, 1 mg/kg) (n = 9) did not reduce neutrophil accumulations in the aspirated segment but limited the remote inflammatory response. CONCLUSIONS: Acid aspiration leads to neutrophil adhesion and edema in regions remote from those aspirated via neutrophil CD18 and endothelial ICAM-1.

Animals↗
PubMed1993

Hypoxia reoxygenation-induced injury of cultured pulmonary microvessel endothelial cells.

Polymorphonuclear leukocyte (PMN) sequestration within the pulmonary microvasculature is known to occur in association with ischemia/reoxygenation (I/R). This sequestration is dependent on eicosanoids and reactive oxygen species. PMN sequestration within the lungs suggests that pulmonary microvascular endothelial cells (MECs) may in part regulate the I/R response. Simulating I/R, we examined the effect of hypoxia/reoxygenation (H/R) on pulmonary MECs in vitro, with and without PMNs. Significant cellular injury, assessed by 51Cr release, occurred upon reoxygenation of MECs (P < .01). Addition of PMNs to the H/R-injured monolayers did not increase MEC injury. Reoxygenation of MECs also resulted in increased thromboxane (Tx) B2 production compared to controls (P < .01). Inhibition of Tx secretion by aspirin reduced H/R-induced PMN adhesion to MECs (P < .01). Furthermore, H/R-induced increases in PMN-MEC adhesion were prevented by allopurinol and superoxide dismutase (P < .01). These data suggest that the pulmonary response to H/R is mediated by MEC generation of reactive oxygen radical species and Tx, which promotes increased PMN adhesion.

Actins↗
PubMed1993

Immunolocalization of cytokeratin 19 in bovine and human pulmonary microvascular endothelial cells in situ.

1. Immunocytochemical analysis of bovine and human lung sections revealed the presence of the 41 kD intermediate filament protein cytokeratin 19 in microvessel and subpleural lymphatic endothelial cells as well as the mesothelial cell layer of the lung visceral pleura. 2. Cytokeratin 19 was expressed by human and bovine pulmonary microvessels with diameters ranging from 5 to 50 microns. 3. Cytokeratin 19 was also found in microvessels of the rete mirabile, an oxygen exchange organ of the eel. 4. Immunoperoxidase electron microscopy demonstrated cytokeratin 19 associated with the lateral membranes of adjacent bovine alveolar capillary endothelial cells.

Animals↗
PubMed1993

Neutrophil and nonneutrophil-mediated injury in intestinal ischemia-reperfusion.

OBJECTIVE: The role of polymorphonuclear neutrophils (PMN) was examined in local and remote organ injury after intestinal ischemia-reperfusion. SUMMARY BACKGROUND DATA: PMN have been found to mediate the local injury in low flow intestinal ischemia-reperfusion. However, in complete intestinal ischemia-reperfusion, prevention of PMN adhesion by monoclonal antibodies to CD11b and CD18 reduces remote but not local intestinal injury. The role of PMN was further investigated in this setting. METHODS: In a rat model of 1-hour complete intestinal ischemia and 4-hour reperfusion. PMN were manipulated in the following four ways: (1) inhibition of oxygen-free radicals using manganese superoxide dismutase and catalase (SOD/CAT), (2) antagonism of PMN elastase using secretory leukocyte protease inhibitor (SLPI), (3) neutropenia using PMN antisera, and (4) inhibition of activation and adhesion using interleukin-1 receptor antagonist (IL-1ra) and tumor necrosis factor binding protein (TNFbp). Lung injury was quantified by the pulmonary permeability index, which is the ratio of bronchoalveolar lavage to blood concentration of radiolabeled bovine serum albumin, and PMN sequestration by myeloperoxidase (MPO) activity. Liver injury was estimated by PMN counts using quantitative histologic examination and by serum glutamic pyruvic transaminase (SGPT). Local injury was quantified by MPO activity and histologic grading. RESULTS: Neutropenia reduced the pulmonary permeability 80% from 11.0 +/- 0.5 x 10(-3) with saline treatment to 5.50 +/- 0.12 x 10(-3); IL-1ra, to 5.62 +/- 0.44 x 10(-3); and TNFbp, to 4.32 +/- 0.18 x 10(-3) (all p < 0.05). Pulmonary MPO rose from 0.03 +/- 0.01 U/g to 0.25 +/- 0.03 U/g (p < 0.05). This was reduced by neutropenia, 0.01 +/- 0.003 U/g, but not by inhibition of oxygen-free radicals or PMN elastase. IL-1ra inhibited PMN sequestration, reducing MPO to 0.12 +/- 0.01 (p < 0.05). Liver injury was 60% dependent on PMN. Ischemia-reperfusion increased SGPT from 20.3 +/- 0.7 IU/L in the sham-treated animals to 97.0 +/- 3.1 IU/L in the experimental animals. Neutropenia reduced this to 48.1 +/- 3.9 IU/L; IL-1ra, to 44.7 +/- 3.7 IU/L; SOD/CAT, to 64.0 +/- 3.38 IU/L; and SLPI, to 57.1 +/- 3.4 IU/L (p < 0.05 in all cases). Local injury was severe and unaffected by manipulation of the PMN. CONCLUSIONS: These data suggest that PMN and their products mediate most of the lung, part of the liver, and none of the local gut injury after intestinal ischemia-reperfusion.

Animals↗
PubMed1993

A CD18 antibody prevents lung injury but not hypotension after intestinal ischemia-reperfusion.

Antibodies to the neutrophil CD18 integrin have been shown to ameliorate the local effects of intestinal ischemia and reperfusion (I/R). In addition to local mucosal injury, intestinal I/R results in systemic hypotension and injury to the lungs with lung leukosequestration. This study tests the effect of a CD18 monoclonal antibody on the hypotension and lung injury after intestinal I/R. In anesthetized rabbits, the superior mesenteric artery was clamped for 60 min followed by 3 h of reperfusion. Animals were treated with saline, an anti-CD18 monoclonal antibody (R15.7 MAb), or nonspecific immunoglobulin G. Another non-ischemic group were sham controls. Neutrophil sequestration was assessed by measure of lung myeloperoxidase (MPO) and permeability by lung-to-blood concentration ratio of 125I-labeled bovine serum albumin and wet-to-dry weight ratio. Immediately after reperfusion, mean arterial pressure fell to 49 +/- 2.1 mmHg and remained at this level. The hypotension was unaffected by treatment with R15.7 MAb. Thirty minutes after reperfusion, the circulating white blood cell count fell to 2.91 +/- 0.53 x 10(3)/mm3 vs. sham 6.40 +/- 0.66 x 10(3)/mm3 (P < 0.05). Treatment with R15.7 MAb prevented this fall in white blood cell count (5.75 +/- 1.59 x 10(3)/mm3). At 3 h of reperfusion in saline-treated animals there was increased MPO, 74.8 +/- 4.9 U/g vs. 42.0 +/- 4.8 U/g in sham animals (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Lavage with leukotriene B4 induces lung generation of tumor necrosis factor-alpha that in turn mediates neutrophil diapedesis.

In experimental models of acute respiratory failure, leukotriene (LT) B4 is generated in the lungs, followed by a 2- to 3-hour delay before there is substantial neutrophil (PMN) accumulation and increased permeability. This study tests whether lavage with LTB4 induces tumor necrosis factor (TNF) synthesis by the lungs that in turn mediates PMN diapedesis. Anesthetized rats underwent lavage with 0.1 ml LTB4 (10(-6) mol/L) into a lung segment. This led to localized TNF synthesis measured in bronchoalveolar lavage fluid with peak concentrations of 580 pg/ml after 1 1/2 hours and 120 pg/ml after 3 hours. These values were higher than after lavage with 0.1 ml saline solution: 0.7 and 4.3 pg/ml, respectively (both p < 0.05). There was a delay before PMN accumulated in bronchoalveolar lavage fluid (x 10(4)). After 30 minutes, the numbers were 2.2 PMN/ml, whereas at 4 hours there was a rise to 40 PMN/ml and at 5 hours 60 PMN/ml, higher than after saline lavage (all p < 0.05). Pretreatment of rats by lavage into airways with actinomycin D, 12 ng in 0.1 ml, minimized LTB4-induced TNF synthesis after 1 1/2 and 3 hours (38 and 51 pg/ml), as well as the delayed diapedesis after 4 hours (12 PMN/ml) (all p < 0.05). Similarly, pretreatment of other rats by lavage with TNF-alpha antiserum (rabbit antimurine), but not normal serum, limited LTB4-induced diapedesis (13 PMN/ml) (p < 0.05). Interestingly, administration of the protein synthesis inhibitor actinomycin D by lavage 10 minutes after LTB4 did not prevent TNF generation after 1 1/2 or 3 hours (490 and 440 pg/ml). However, this agent did limit PMN diapedesis after 4 hours (14 PMN/ml) (p < 0.05), an event possibly caused by limiting later synthesis of endothelial adhesion proteins, a thesis consistent with the findings that pretreatment of rats by lavage with actinomycin D was without any effect on N-formyl-methionyl-phenylalanine (10(-8) mol/L)-induced diapedesis. This agent is known to induce PMN migration without need for synthesis of endothelial adhesion proteins. The data indicate that lavage with LTB4 induces local TNF-alpha generation that in turn mediates a delayed PMN diapedesis. This event is likely regulated by endothelial synthesis of adhesion proteins.

Animals↗
PubMed1993

Leukocytes mediate acid aspiration-induced multiorgan edema.

BACKGROUND: Acid aspiration leads to lung injury characterized by polymorphonuclear neutrophil leukocytes (PMN) sequestration and edema. This study investigates whether localized acid aspiration leads to activation of circulating PMN and triggers both local and remote PMN sequestration and whether these cells are responsible for increase in pulmonary permeability and systemic organ edema. METHODS: Rats pretreated with intravenous saline solution or rendered neutropenic (nitrogen mustard or antineutrophil serum) underwent tracheostomy and insertion of a cannula into a lung segment. This was followed by instillation of either 0.1 N HCl or saline solution. RESULTS: After 30 minutes leukopenia was noted (2650 white blood cells/mm3) in saline-treated, acid-lavaged rats, and circulating PMN produced H2O2 (20 femtomole dichlorofluorescein/PMN compared with 3 femtomole in control animals (both, p < 0.05). PMN were progressively sequestered in the nonaspirated lung, the heart, and kidney. Permeability and edema developed in the lungs and systemic organs. In neutropenic rats there was a reduction of aspiration-induced thromboxane B2 and leukotriene B4 synthesis (p < 0.05), decrease in lung wet to dry weight and protein level in bronchoalveolar lavage of the aspirated and nonaspirated lungs, and reduction in myeloperoxidase activity in the heart and kidney and in wet to dry weight of these organs (all, p < 0.05). CONCLUSIONS: These data indicate that localized acid aspiration activates circulating neutrophils and promotes their sequestration in the lungs and systemic organs. These cells are largely responsible for the multisystem organ edema.

Animals↗
PubMed1992

Soluble complement receptor type 1 ameliorates the local and remote organ injury after intestinal ischemia-reperfusion in the rat.

We examined the role of C activation in ischemia reperfusion injury by inhibiting C activation in a rat model of mesenteric arterial occlusion. In anesthetized rats, 60 min of mesenteric arterial occlusion was followed by 3 h of reperfusion. PBS alone or containing soluble C receptor 1 (3 or 6 mg) was administered i.v. Controls underwent laparotomy without ischemia. Relative serum C activities were assessed by hemolytic assay, neutrophil (polymorphonuclear leukocyte) sequestration by tissue content of myeloperoxidase (MPO) activity, intestinal mucosal injury by histologic grading, lung vascular permeability by the ratio of bronchoalveolar lavage to blood concentration of radiolabeled BSA, and endothelial cell injury was quantified by measurement of plasma factor VIII-related Ag. After reperfusion, PBS-treated animals had increased intestinal MPO (0.048 +/- 0.007 U/g) compared to sham (0.022 +/- 0.005 U/g (p less than 0.05)) and intestinal mucosal injury score (2.490 +/- 0.221) compared to sham (0.331 +/- 0.045 (p less than 0.05)). Treatment with 6 mg soluble C receptor 1 15 min before reperfusion reduced intestinal MPO (0.017 +/- 0.003 U/g (p less than 0.05)) and mucosal injury (1.733 +/- 0.168 (p less than 0.05)) compared to PBS control. PBS-treated animals also demonstrated increased lung MPO (0.314 +/- 0.025 U/g vs 0.085 +/- 0.018 in sham (p less than 0.05)) and increased lung permeability (bronchoalveolar lavage/blood cpm 11.32 +/- 1.35 x 10(-3) vs sham 2.22 +/- 0.19 x 10(-3) (p less than 0.05)). Treatment with 6 mg soluble C receptor 1 15 min before reperfusion or at reperfusion reduced the lung permeability (bronchoalveolar lavage/blood cpm 3.90 +/- 0.79 x 10(-3) and 5.08 +/- 0.75, respectively (both p less than 0.05)) compared to PBS control, but did not reduce lung MPO (0.342 +/- 0.031 U/g and 0.246 +/- 0.025), respectively. Treatment with sCR1 also reduced the release of factor VIII-related Ag, 5-day mortality, and C hemolytic activity. In this model, C is a major mediator of intestinal injury and extraintestinal injury.

Animals↗
PubMed1992

Adherent neutrophils mediate permeability after atelectasis.

Re-expansion of atelectatic lung is associated with increased permeability. This study tests whether neutrophils mediate this event. Right middle lobar atelectasis was induced in anesthesized rabbits (n = 18) by intraluminal obstruction of the bronchus after a 20-minute ventilation with 100% O2. After 1 hour of bronchial obstruction and 20 minutes after lobar re-expansion, leukopenia was noted, 2870 +/- 210 white blood cells (WBC)/mm3, relative to control animals treated with a noninflated balloon catheter, 6500 +/- 410 WBC/mm3 (p less than 0.05). Three hours after re-expansion, neutrophils were sequestered in the previously atelectatic region 78 +/- 7 polymorphonuclear leukocytes (PMN)/10 high-power field (HPF), as well as in nonatelectatic areas, 40 +/- 3 PMN/10 HPF, higher than control values of 26 +/- 3 PMN/10 HPF (p less than 0.05). In the atelectatic region, neutrophil sequestration was associated with increased protein concentration in lobar bronchoalveolar lavage (BAL) of 1370 +/- 100 micrograms/mL, higher than control values of 270 +/- 20 micrograms/mL (p less than 0.05). Reexpansion also induced increases in lung wet-to-dry weight ratio (W/d) of 6.2 +/- 0.2, higher than control values of 4.3 +/- 0.1 (p less than 0.05). Rendering rabbits neutropenic (n = 18) (0 to 4 PMN/mm3) limited the atelectasis-induced protein accumulations in BAL (520 +/- 60 micrograms/mL) and increase in lung W/d (5.2 +/- 0.1) (both p less than 0.05). Intravenous (I.V.; treatment of another group (n = 18) with an anti-CD 18 monoclonal antibody (R 15.7, 1 mg/kg) before balloon deflation prevented leukopenia (6550 +/- 560 WBC/mm3), minimized neutrophil sequestration (36 +/- 2 PMN/10 HPF), and attenuated protein leak (710 +/- 95 micrograms/mL) and the increased lung W/d (5.6 +/- 0.1) (all p less than 0.05). A final atelectatic group (n = 9) was treated I.V. with the anti-intercellular adhesion molecule-1 monoclonal antibody (RR 1/1, 1 mg/kg), which also prevented leukopenia and showed similar protection of microvascular barrier function. These data indicate that adherent neutrophils in large part mediate lung permeability and edema after atelectasis and re-expansion. Adhesion receptors of both neutrophils and endothelial cells regulate this event.

Animals↗
PubMed1992

Blockade of complement activation prevents local and pulmonary albumin leak after lower torso ischemia-reperfusion.

Lower torso ischemia and reperfusion leads to both local and remote tissue injuries. The purpose of this study was to assess the role of complement in mediating the local and remote microvascular permeability after bilateral hind limb tourniquet ischemia. Four hours of ischemia and 4 hours of reperfusion produced an increased skeletal muscle permeability index (muscle/blood 125I albumin ratio) of 2.90 +/- 0.35 compared with the index in nonischemic muscle of 0.25 +/- 0.02 (p < 0.01). Muscle wet-to-dry-weight ratio increased from 3.93 +/- 0.04 in sham to 5.55 +/- 0.09 in ischemic muscle (p < 0.0001). Lung permeability rose at 4 hours as indicated by the increased bronchoalveolar lavage (BAL)/blood 125I albumin ratio 4.36 +/- 0.41 x 10(-3) versus sham 2.64 +/- 0.28 x 10(-3) (p < 0.05) and neutrophil sequestration 0.28 +/- 0.02 U/g myeloperoxidase (MPO) versus sham 0.14 +/- 0.02 U/g (p < 0.001). Serum lytic activity of the classical but not the alternate complement pathway was reduced. The soluble complement receptor (sCR1) was used to inhibit complement activity and attenuated the increase in the permeability index after reperfusion in ischemic muscle 1.11 +/- 0.08 (p < 0.01) and reduced the lung BAL/blood 125I albumin ratio to sham levels 2.46 +/- 0.39 x 10(-3) (p < 0.05) at 6 mg/animal, without reducing the lung neutrophil sequestration, 0.24 +/- 0.02 U/g. The authors conclude that complement activation occurred during tourniquet ischemia and mediated permeability changes in the ischemic muscle and the lungs during reperfusion.

Albumins↗
PubMed1992

Reactive oxygen species and elastase mediate lung permeability after acid aspiration.

Acid aspiration leads to increased neutrophil (PMN) oxidative metabolism, an event associated with lung leukosequestration and permeability increase. Neutropenia protected the vascular barrier function against acid injury. This study tests whether active oxygen species and elastase (which are presumably released by adherent PMNs) affect the microvascular barrier. Anesthetized rats underwent tracheostomy and insertion of a cannula into a lung segment. This was followed by localized instillation of 0.1 N HCl (n = 18) or saline (n = 18). Sequestration of PMNs in acid-aspirated and nonaspirated segments was 77 and 46 PMNs/high-power field (HPF), respectively, which was higher than control values of 11 and 8 PMNs/10 HPF in saline-aspirated and nonaspirated regions (P less than 0.05). Acid aspiration was associated with increased protein concentration in bronchoalveolar lavage (BAL) fluid to 3,550 and 2,900 micrograms/ml in the aspirated and nonaspirated lungs, respectively, which were higher than control values of 420 and 400 micrograms/ml (P less than 0.05). Acid aspiration also led to increased lung wet-to-dry weight ratios (W/D) of 6.6 and 5.4, which were higher than control values of 3.4 and 3.3 (P less than 0.05). Intravenous treatment of rats (n = 18) 90 min after aspiration with scavengers of reactive oxygen species, superoxide dismutase (1,500 U/kg), and catalase (5,000 U/kg), both conjugated to polyethylene glycol, did not reduce PMN sequestration but attenuated acid aspiration-induced increase in protein accumulation in BAL fluid in the aspirated and nonaspirated segments (990 and 610 micrograms/ml) as well as the increased lung W/D (4.6 and 4.0; all P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Role of neutrophil adherence receptors (CD 18) in lung permeability following lower torso ischemia.

Ischemia and reperfusion of the lower torso lead to leukotriene- and neutrophil (PMN)-dependent lung injury characterized by lung PMN sequestration, increased permeability, and noncardiogenic edema. It is thought that PMNs require adhesion to endothelium to alter barrier function. This study tests the role of CD 18, the PMN adherence receptor, in mediating lung permeability after lower torso ischemia and reperfusion. Anesthetized rabbits (n = 9) underwent 3 hours of bilateral hind limb ischemia. Ten minutes after the release of the tourniquets, plasma leukotriene B4 levels increased to 395 +/- 85 pg/ml, higher than 129 +/- 35 pg/ml in controls (n = 9, p less than 0.01). At this time there was a reduction in circulating white blood cells (x 10(3)), 3.56 +/- 0.49/mm3 relative to 6.07 +/- 0.61/mm3 in controls (p less than 0.01). PMNs were sequestered in the hind limbs, indicated by increased myeloperoxidase activity of 1.06 +/- 0.19 units/g compared with 0.56 +/- 0.09 units/g in controls (p less than 0.05). Four hours after tourniquet release, PMNs were sequestered in the lungs, 52 +/- 4 PMNs per 10 high-power fields, a value higher than 31.5 +/- 3 PMNs per 10 high-power fields in controls; bronchoalveolar lavage fluid protein content increased to 554 +/- 90 micrograms/ml relative to 277 +/- 46 micrograms/ml in controls; and there was lung edema, measured by increased wet weight-to-dry weight ratios of 5.19 +/- 0.10, higher than 4.29 +/- 0.21 in controls (all p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Synergism between leukotriene B4 and thromboxane A2 in mediating acid-aspiration injury.

Acid aspiration leads to thromboxane-dependent lung neutrophil sequestration associated with microvascular permeability increase. Leukotriene B4 (LTB4) is postulated to be a cofactor in the thromboxane-induced inflammatory response. This study tests the interaction between LTB4 and thromboxane, focusing on LTB4 induction of thromboxane-dependent lung neutrophil sequestration after acid aspiration. Anesthetized rats underwent tracheostomy and insertion of a cannula in a left lung segment. This was followed by instillation of either 0.1 ml 0.1N hydrochloric acid (n = 18) or 0.1 ml saline in control rats (n = 18). When assayed at 3 hours, acid aspiration led to increased plasma levels of LTB4 and thromboxane B2 (TxB2), higher than control values (p less than 0.05). The rise in plasma LTB4 was correlated (p less than 0.05; r = 0.83) with sequestration of neutrophils in the nonaspirated lung. The entrapment of thromboxane-dependent lung neutrophil was associated with an increase in protein concentration in bronchoalveolar lavage of the aspirated and nonaspirated sides and an increase in lung wet to dry weight ratio. Pretreatment of other rats (n = 18) with the lipoxygenase inhibitor diethylcarbamazine IV prevented an aspiration-induced rise in plasma LTB4 and TxB2. Further, there was an attenuation of lung leukosequestration and protein leak in bronchoalveolar lavage and lung edema (all p less than 0.05). Pretreatment of other rats (n = 12) with the leukotriene receptor antagonist FPL 55712 IV did not prevent the aspiration-induced rise in LTB4 or TxB2, but otherwise was as effective as diethylcarbamazine in preventing injury. Finally, other hydrochloric acid-aspirated rats (n = 8) were pretreated intravenously with the thromboxane synthetase inhibitor OKY 046 or the thromboxane receptor antagonist SQ 29548. Both agents limited the aspiration-induced rise in plasma LTB4 (p less than 0.05). The data indicate that localized acid aspiration induces synthesis of LTB4 and thromboxane A2. Inhibition of either leukotriene or thromboxane will limit PMN adhesion and increased lung permeability.

Animals↗