Biomedical subjects

D D Bensard

Publications and source records attributed to D D Bensard.

At least 37 records · Page 2Linked to original sources

PubMed1996

Long-term results with the Kasai operation for biliary atresia.

OBJECTIVE: To evaluate long-term outcome in a series of children with biliary results atresia treated by portoenterostomy. DESIGN: Case series of consecutive infants with biliary atresia with 10-year follow-up. Data were obtained by retrospective chart review or phone interview. SETTING: A tertiary academic medical center and regional children's hospital. PATIENTS: A consecutive series of 104 infants diagnosed with biliary atresia more than 10 years ago were evaluated. Eighty-nine had totally obliterated extrahepatic ducts, 4 had proximal hilar cysts (correctable type), and 11 had patency of the gallbladder and distal common duct. INTERVENTIONS: Ninety-eight patients underwent biliary reconstruction and 6 had exploration only. Seventy-four infants underwent reconstruction using a Rouxen-Y with exteriorization. The 11 infants with distal patency underwent a portocholecystostomy ("gallbladder Kasai"). The remainder had various modifications of the Kasai operation. MAIN OUTCOME MEASURES: Survival, liver function, complications, growth, and development. RESULTS: The 6 patients who did not have a portoenterostomy died. Of the 98 who had a reconstruction, 63 died (mean age at death, 27 months; median, 13.4 months), 10 following liver transplantation. Twelve of the 35 survivors ultimately required liver transplants. Twenty-three children are alive more than 10 years after portoenterostomy without the need for transplantation. Two thirds have experienced some manifestation of portal hypertension (ie, variceal bleeding, hypersplenism, ascites). Nineteen patients (79%) are anicteric with normal liver synthetic function and are in an age-appropriate school grade or working and living independently. CONCLUSIONS: We found that surgical correction of biliary atresia offers long-term survival for about one quarter of patients, provides palliation until liver transplantation becomes necessary, and if surgical correction is not feasible, biliary atresia is uniformly fatal. The outlook is good for those children who survived more than 10 years and justifies continued attempts to establish bile flow in infants with biliary atresia.

Adolescent↗

PubMed1996

Exposure for laparoscopic cholecystectomy dissection adversely alters biliary ductal anatomy.

BACKGROUND: Exposure for open cholecystectomy entails lateral, caudal traction on the gallbladder infundibulum, which results in opening the angle between the cystic and hepatic ducts. Laparoscopic cholecystectomy (LC), as initially described, is done with cephalad traction on the gallbladder. We hypothesized LC exposure technique narrows the angle between the cystic and hepatic ducts, placing them at increased risk of injury. METHODS: Twenty-three patients had routine LC. Cystic duct cholangiography (IOC) was done with a flexible 5-Fr catheter via a percutaneous introducer placed anterior to the gallbladder. Exposure of Calot's triangle was maintained with cephalad traction on the gallbladder fundus. IOC was repeated after allowing the organ to assume the anatomic position. The cholangiograms were inspected for significant differences, and the angle of the cystic to the hepatic duct (CDHD) was measured by a blinded radiologist. RESULTS: The mean angle of the cystic to hepatic duct was 30 degrees +/- 19 degrees in the IOCs taken with cephalad traction on the gallbladder fundus vs 59 degrees +/- 22 degrees, P < 0.001, in the cholangiograms taken without traction. A filling defect at the cystic-hepatic duct junction was present in 39% of IOC taken with traction vs none without traction. The intrahepatic ducts were seen in all films without traction, whereas the intrahepatic ducts were not visualized in 13% of IOCs taken with traction. CONCLUSIONS: From these data we conclude (1) extra-hepatic biliary ducts may be at increased risk of injury during LC because of the exposure technique and (2) imaging bile ducts in the anatomic position may convey misleading information about the relative location of important structures. Optimal exposure for dissection of Calot's triangle should utilize a second clamp on the infundibulum with lateral, caudal traction.

Bile Ducts, Intrahepatic↗

PubMed1996

Laparoscopic evaluation of contralateral patent processus vaginalis in children.

BACKGROUND: Routine contralateral inguinal exploration following unilateral herniorrhaphy in children remains controversial. Contralateral patent processus vaginalis (PPV) incidence decreases from 80% in young infants to about 20% to 30% in the adult population. However, the incidence of a clinical hernia appearing subsequently following unilateral herniorrhaphy is 6% to 10%. METHODS: Fifty consecutive children were evaluated by diagnostic laparoscopy (DL) at the time of inguinal herniorrhaphy. RESULTS: The mean age was 3 years. Thirteen of 42 patients (31%) with a symptomatic confirmed hernia had a contralateral PPV by DL. The mean operating time was 48 minutes. The sensitivity was 98% with a specificity of 100%. No child suffered a complication due to DL. CONCLUSIONS: We found diagnostic laparoscopy in children with evidence of unilateral inguinal hernia (1) was safe, (2) revealed a 31% incidence of contralateral PPV, and (3) eliminated the need for contralateral exploration in 69%.

Child↗

PubMed1996

Small bowel injury in children after blunt abdominal trauma: is diagnostic delay important?

OBJECTIVE: To assess the incidence and consequences of small bowel injury (SBI) in children suffering blunt abdominal trauma managed with the intent to treat nonoperatively. DESIGN: Retrospective chart review. MATERIALS AND METHODS: A total of 168 consecutive hemodynamically stable children admitted to a Level I pediatric trauma center during a 24-month period. RESULTS: Nine of 168 children (5%) sustained SBI: three underwent early (< 4 hours) operation for recognized SBI (identified on computed tomographic scan); and six had delayed (36 +/- 16 hours) operation for missed SBI (not identified on computed tomographic scan). Increased temperature and heart rate, or decreased urine output at 24 hours suggested occult SBI. The hospital course was unaltered by delayed diagnosis. Fifty-seven percent of the children (95) suffered intra-abdominal injury; 10% required laparotomy for SBI (9) or solid organ injury (7); 90% (152) were discharged without laparotomy. CONCLUSIONS: SBI is uncommon in children suffering blunt abdominal trauma. The diagnosis can be made using clinical and radiographic findings. Limited diagnostic delay does not seem to affect outcome. We conclude that clinical diagnosis of SBI is safe, permits the nonoperative treatment of most blunt abdominal injuries, and reduces the risk of unnecessary laparotomy associated with alternate approaches.

Abdominal Injuries↗

PubMed1995

Preoperative cardiac risk management.

CAD is present in most patients with peripheral arterial disease and is the leading cause of morbidity and mortality after vascular operations. Clinical risk assessment attempts to identify those patients at low, intermediate, or high cardiac risk for adverse cardiac outcomes. Additional tests add little information to the estimates obtained by clinical scoring in patients at low risk. Patients with high cardiac risk scores are clearly at increased risk of experiencing postoperative complications, but further investigations are needed only if knowledge of the functional severity or degree of myocardial ischemia will alter subsequent management. In general, high-risk patients should proceed to coronary angiography, intensive perioperative monitoring, alteration in the planned operation, or avoidance of surgery altogether if indications are less than compelling. Those patients identified as intermediate risk by clinical scoring benefit most from additional tests. In these patients special studies or even coronary arteriography may be useful if the vascular surgery can be delayed until myocardial revascularization is completed. Practically, preoperative cardiac work-up must also consider the indication for surgery. Patients who have threatened limbs or ruptured aneurysms or are severely symptomatic cannot afford the time involved for obtaining additional tests. Moreover, the question of what to do with the information provided by special studies is problematic in these patients. For example, if significant symptomatic or asymptomatic CAD is present in a patient with a gangrenous foot, what is gained by the delay in lower extremity revascularization required when prophylactic CABG is performed? Reports supporting prophylactic CAD intervention are nonrandomized and uncontrolled. CABG and PTCA should be performed only on the merits of the patient's cardiac symptoms and coronary artery anatomy, not to enhance safety of the proposed vascular procedure, because advances in surgical and anesthetic techniques and intraoperative and postoperative monitoring have resulted in lower morbidity and mortality of elective vascular surgery.

Arterial Occlusive Diseases↗

PubMed1994

Endotoxin disrupts beta-adrenergic signal transduction in the heart.

BACKGROUND: Nonsurvivors of septic shock demonstrate impaired myocardial function refractory to the administration of beta-agonists. METHODS: Using the isolated rat heart preparation, the integrity of the beta-adrenergic transduction pathway was tested (rate pressure product, rate of contraction, rate of relaxation, and cyclic adenosine monophosphate content) using isoproterenol hydrochloride (beta-receptor agonist) or colforsin (forskolin) (adenylyl cyclase activator) stimulation following intracoronary endotoxin infusion. RESULTS: Basal rate pressure product, rate of contraction, rate of relaxation, and cyclic adenosine monophosphate concentrations were unaffected by endotoxin infusion. Endotoxin impaired, increases in rate pressure product, rates of contraction and relaxation, and cyclic adenosine monophosphate to isoproterenol (P < .05), but the response to colforsin was unaffected by endotoxin. CONCLUSIONS: Endotoxin disrupts the myocardial response to direct beta-receptor stimulation but not to adenylyl cyclase stimulation in the isolated rat heart. CLINICAL RELEVANCE: Alteration of the proximal beta-adrenoreceptor complex by endotoxin suggests that therapy of the failing heart during refractory septic shock may be directed to intact sites distal in the beta-adrenergic pathway.

Adenylyl Cyclases↗

PubMed1994

A critical analysis of acutely injured children managed in an adult level I trauma center.

The triage of all injured children to regional pediatric trauma centers may be impractical and unnecessarily exclude adult level I trauma centers from the care of the acutely injured child. The purpose of this study was to critically evaluate the outcome of injured children treated in an adult level I trauma center by adult trauma surgeons. The records of 410 consecutively treated children (age < or = 15 years) and 188 young adults (age 16 to 18 years) admitted to the trauma service during a 2-year period (ending December 1991) were studied. The probability of survival was calculated using TRISS methodology. Results were analyzed using the Z statistic, permitting objective comparison with national norms (Major Trauma Outcome Study). Severity of injury (RTS and ISS) was equivalent (P > .05) in children and young adults. The observed survival (98.0%) in children compared favorably with the predicted survival (TRISS) of 97.7%. Calculation of the Z statistic showed no difference in outcomes of acutely injured children (+0.47) relative to young adults (+0.45) or national norms (MTOS). The triage of injured children to an adult level I trauma center does not adversely affect outcome. Subset analysis of injured children showed no differences in observed outcome relative to predicted outcome (national control) or outcome in young adults (institutional control). These data support the continued triage of acutely injured children to regional trauma centers regardless of pediatric or adult designation.

Acute Disease↗

PubMed1994

Adenosine A1-receptor mechanisms antagonize beta-adrenergic pulmonary vasodilation in hypoxia.

Hypoxic pulmonary vasoconstriction is refractory to beta-adrenergic receptor (beta-AR)-mediated pulmonary vasodilation. We hypothesized that hypoxic pulmonary arteries release adenosine (Ado) that antagonizes beta-AR-mediated pulmonary vasodilation. Using isolated rat pulmonary artery rings, we investigated 1) the effect of hypoxia and exogenous Ado on beta-AR-mediated pulmonary vasodilation, 2) the intracellular site of dysfunctional beta-AR-mediated pulmonary vasodilation in hypoxia, and 3) the Ado receptor subtype responsible for dysfunction of beta-AR-mediated pulmonary vasodilation. Hypoxia attenuated normal beta-AR-mediated pulmonary vasodilation to isoproterenol (97.5 +/- 0.8 vs. 71.5 +/- 2.3%, P < 0.01). In contrast, forskolin induced the same vasorelaxation in hypoxic pulmonary rings as controls (P = 0.09). Incubation of normoxic rings with Ado attenuated the vasorelaxation response induced by beta-AR stimulation (71.5 +/- 5.9%, P < 0.01), similar to the effect observed in hypoxia. Both nonspecific Ado receptor blockade (8-sulfophenyl-theophylline) and specific A1-receptor blockade (8-cyclopentyl-1,3-dimethylxanthine) restored the vasorelaxation response of hypoxic rings induced by beta-AR stimulation (93.3 +/- 2.3 and 92.2 +/- 2.8%, P < 0.01). The effects of hypoxia and Ado were reproduced by a specific A1 agonist (2-chloro-N6-cyclopentyladenosine), demonstrating impaired vasorelaxation induced by beta-AR stimulation in normoxia (70.6 +/- 4.5%, P < 0.01). From these data, we conclude that hypoxia antagonizes beta-AR-mediated pulmonary vasodilation via an Ado A1-receptor mechanism.

Adenosine↗

PubMed1994

The pediatric diaphragm in acute gastric volvulus.

Acute gastric volvulus occurred in nine infants and one older child during the past 19 years; all patients had an associated left diaphragmatic anomaly. There were seven examples of eventration of the diaphragm, two of giant hiatal hernia and one Bochdalek hernia. Nine of the ten patients presented with vomiting and one with acute respiratory distress. The gastric volvulus was mesenteroaxial in eight patients and organoaxial in two. Operative treatment consisted of repair of the diaphragmatic anomaly and gastric fixation in eight patients. Gastric fixation alone was performed in one patient. A single patient died preoperatively and had gastric necrosis at postmortem examination. Of the nine patients treated operatively, all remain alive and well without recurrence. Acute gastric volvulus should be considered in any infant presenting with unexplained vomiting in association with a left diaphragm anomaly, and once diagnosed, immediate operation is mandatory.

Acute Disease↗

PubMed1993

Pelvic fracture geometry predicts risk of life-threatening hemorrhage in children.

Recent studies have concluded that pelvic fractures in children, unlike those in adults, are not a source of life-threatening hemorrhage. Our study hypothesis was that major bleeding occurs in children with pelvic fractures, and fracture geometry allows early identification of patients at risk for severe hemorrhage. Fifty-seven (5.5%) of 1044 pediatric trauma patients sustained pelvic fractures. The majority of injuries were from motor vehicle crashes (n = 21, 36.8%) and auto-pedestrian collisions (n = 18, 31.6%). Twenty-three children (40.4%) had unilateral anterior fractures (type I), seven (12.2%) had unilateral posterior fractures (type II), 23 (40.4%) had unilateral anterior and posterior fractures (type III), and four (7%) had bilateral anterior and posterior (type IV) fractures. Eighteen children (32.6%) required blood transfusions during the initial 48 hours (mean, 59 mL/kg). Skeletal fixation was applied in ten patients (17.5%), and it controlled bleeding in six (60%). Pelvic angiography identified arterial hemorrhage in three of four patients, and embolization controlled bleeding in all cases. The only death in the series (mortality, 1.7%) was from multisystem trauma. Age, sex, Injury Severity Score, Revised Trauma Score, mechanism of injury, and pelvic fracture geometry were evaluated as risk factors predictive of hemorrhage employing multiple logistic regression. Only pelvic fracture geometry independently identified patients at increased risk of major bleeding. We conclude that pelvic fracture geometry identifies a subset of pediatric trauma patients at high risk for life-threatening hemorrhage and urge a prompt multispecialty approach to these patients.

Accidents, Traffic↗

PubMed1993

Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism.

Preconditioning may find ready applicability in humans facing scheduled global cardiac ischemia-reperfusion (IR) during bypass or transplantation, where such a maneuver is feasible before arrest. Our objective was to delineate and exploit the endogenous preconditioning mechanism triggered by transient ischemia (TI) and thereby attenuate myocardial postischemic mechanical dysfunction by clinically acceptable means. Preconditioning by 2 minutes of TI followed by 10 minutes of normal perfusion protected isolated rat left ventricle function assessed after 20 minutes of global, 37 degrees C ischemia and 40 minutes of reperfusion. Final recovery of developed pressure (DP) was improved (91.5 +/- 1.9% of equilibration DP versus unconditioned IR control, 57.4 +/- 2.4%, P < .01) and was accompanied by increased contractility (+/- dP/dt). Norepinephrine release increased after TI, and reserpine pretreatment abolished TI preconditioning. This suggests that endogenous norepinephrine mediates functional preconditioning in rat. Brief pretreatment (2 minutes) with exogenous norepinephrine reproduced the protection (89.1 +/- 1.4%) of postischemic function. Functional protection persisted after the hemodynamic effects had resolved. Norepinephrine-induced preconditioning was simulated by phenylephrine and blocked by alpha 1-adrenergic receptor antagonist. TI preconditioning was similarly lost after selective alpha 1-adrenergic receptor blockade. We conclude that transient ischemic preconditioning is mediated by the sympathetic neurotransmitter release and alpha 1-adrenergic receptor stimulation. Although the postreceptor mechanism remains unclear, functional protection after IR does not seem related to the magnitude of ATP depletion and elevation of resting pressure during ischemia. Rather, the endogenous mechanisms facilitate both recovery of mechanical function and ATP repletion during reperfusion.

Animals↗

PubMed1993

Comparison of video thoracoscopic lung biopsy to open lung biopsy in the diagnosis of interstitial lung disease.

BACKGROUND: Up to one third of patients with interstitial lung disease will require a lung biopsy for diagnosis. Open lung biopsy is generally accepted as the most reliable method of biopsy and tissue diagnosis. The purpose of this study was to compare the efficacy and safety of video thoracoscopic lung biopsy, a minimally invasive technique, with open lung biopsy in the diagnosis of interstitial lung disease. METHODS: From December 1990 to January 1992, 43 patients were referred for diagnostic lung biopsy. Twenty-two consecutive patients undergoing video thoracoscopic lung biopsy (VTLB) over a 6-month period were retrospectively studied and compared with 21 consecutive patients who had undergone open lung biopsy (OLB) in the preceding 6-month period. RESULTS: VTLB (46 +/- 4 minutes) did not add to operative time when compared with OLB (38 +/- 3 min, p = 0.09). The same number of biopsies per patient were performed (VTLB, 1.9 +/- 0.1; OLB, 2.0 +/- 0.1; p = 0.48), the same amount of tissue was obtained per biopsy (VTLB, 6.69 +/- 0.82 cm3; OLB, 5.78 +/- 0.54 cm3; p = 0.36), and the diagnostic accuracy of each method was comparable (VTLB, 95 percent; OLB, 100 percent). However, patients undergoing VTLB demonstrated a significant reduction in length of pleural drainage (1.36 +/- 0.25 days) and hospital stay (2.57 +/- 0.46 days) relative to patients undergoing OLB (3.20 +/- 0.34 days, 5.71 +/- 0.63 days; p < 0.05). Complications occurred in 2/22 VTLB patients (9 percent, 0 deaths) and 4/21 OLB patients (19 percent, 1 death). CONCLUSIONS: When compared with OLB, VTLB does the following: (1) provides equivalent specimen volume; (2) achieves equal diagnostic accuracy; (3) does not add to operative time or complications; and (4) reduces the time necessary for pleural drainage and length of hospital stay. Our findings suggest that VTLB is an effective and safe alternative to OLB in the diagnosis of interstitial lung disease.

Adult↗

PubMed1992

Liver injury is a reversible neutrophil-mediated event following gut ischemia.

The purposes of this study were to characterize the temporal relationship of distant organ dysfunction after mesenteric ischemia/reperfusion (I/R), and to ascertain if the neutrophil is critical to this process. Normal and neutrophil-depleted rats (vinblastine sulfate, 0.75 mg/kg intravenously) underwent 45 minutes of superior mesenteric artery occlusion and after 0, 6, and 18 hours of reperfusion, blood was sampled and liver and lungs were harvested. Iodine 125 albumin leak was used as a marker for pulmonary and liver injury, and serum acetoacetate/3-hydroxybutyrate (AcAc/3-OHB) was used as an index of hepatic mitochondrial redox state. Gut I/R at 6 hours increased 125I-albumin lung/blood ratio (gut I/R, 0.077 +/- 0.006; control, 0.045 +/- 0.004) and 125I-albumin liver/blood ratio (gut I/R, 0.120 +/- 0.007; control, 0.077 +/- 0.003), while AcAc/3-OHB decreased significantly (gut I/R, 0.420 +/- 0.040; control, 0.880 +/- 0.120). Neutrophil depletion eliminated these changes at 6 hours (blood AcAc/3-OHB, 0.720 +/- 0.100; 125I liver/blood, 0.068 +/- 0.006; 125I lung/blood, 0.046 +/- 0.007). We conclude the following: (1) intestinal I/R produces simultaneous liver and lung injury; (2) injury was present at 6 hours but is reversed at 18 hours; and (3) the I/R-induced liver and lung injuries were neutrophil mediated.

Animals↗

PubMed1992

Neutrophils contribute to TNF induced myocardial tolerance to ischaemia.

Sublethal endotoxin (ETX) pretreatment of rats induces protection from cardiac ischaemia-reperfusion injury. This protective state is associated with increased endogenous myocardial catalase activity. Since tumour necrosis factor (TNF) is one mediator of ETX effects, we hypothesized that (TNF) pretreatment of the rat (30 micrograms/kg ip) 36 h prior to cardiac ischaemia-reperfusion could induce myocardial protection. We found that TNF administration increased both myocardial tolerance to ischaemia reperfusion injury (modified Langendorff, buffer perfusion, global, normothermic ischaemia) and myocardial catalase activity at 36 h. Moreover, we found that 6 h after TNF administration, myocardial hydrogen peroxide (H2O2, assessed by aminotriazole-H2O2 inactivation of catalase) and myocardial neutrophil accumulation (assessed by histology) were both increased. When neutrophil function was inhibited either by neutrophil depletion (vinblastine) or by ibuprofen treatments of the rat before TNF, the protection previously apparent at 36 h was blocked. We conclude that TNF can induce myocardial resistance to ischaemia reperfusion injury. This protection is related to prior tissue neutrophil accumulation and concomitant increases in H2O2 levels.

Animals↗

PubMed1992

Platelet activating factor alters receptor-coupled function in the isolated perfused rat heart.

Sepsis induces primary myocardial dysfunction. Yet, both hyper- and hypodynamic cardiac states characterize the sepsis syndrome, suggesting a modulatory role of septic mediators. Platelet activating factor (PAF), implicated in the pathogenesis of sepsis, is an endogenous phospholipid with diverse intracellular and extracellular effects. The purpose of this study was to investigate the influence of PAF (1) upon basal mechanical function of the heart, (2) upon receptor-coupled function of the heart, and (3) on basal and stimulated myocardial function at differing concentrations. In order to focus on the relationship between PAF and cardiac mechanical function, rat hearts were isolated and crystalloid perfused using a modified Langendorf preparation. Separate hearts received intracoronary vehicle (5% ethanol, 2.5% BSA) or PAF (20 or 40 microM) as a bolus, followed 10 min later by 0.25 microM isoproterenol (beta-receptor agonist) infusion over 3 min. Both 20 and 40 microM PAF produced a rapid decrease in rate pressure product (RPP = HR X LVDPmax) relative to control (P < 0.05). The depressive effect of PAF upon basal myocardial function did not persist and by 10 min RPP was not different (P > 0.05) among the groups. Isoproterenol infusion increased (P < 0.05) RPP in all groups. However, hearts pretreated with 20 microM PAF demonstrated a greater (P < 0.05) response to beta-adrenergic stimulation relative to vehicle-pretreated controls. This amplified response to isoproterenol was not observed with pretreatment at a higher concentration of PAF (40 microM, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Gut and liver coordinated metabolic response following major torso injury.

Major trauma provokes a stress response which is mediated, in part, via glucagon, catecholamines, and cortisol. These stress hormones modulate the choice of energy substrate for various tissues. While glucose and fatty acids are considered the preferred fuels, ketone bodies (26/ATP/mole) may be a viable alternative. In this study, we measured the concentrations of acetoacetate and beta-hydroxybutyrate (3-OHB) in the portal as well as systemic circulations of 10 critically injured patients (revised trauma score = 6.8 +/- 0.5, injury severity score = 27 +/- 3) during the first 5 postoperative days. At 6 hr postinjury, 3-OHB was elevated in the portal system (0.34 +/- 0.01 mM) while depressed systemically (0.09 +/- 0.02 mM), indicating that the gut was capable of ketogenesis. In contrast, at 24 hr, 3-OHB rose systemically (0.39 +/- 0.02 mM) while decreasing in portal blood (0.09 +/- 0.01 mM) implying gut ketone consumption. Moreover, the systemic ketone body ratio became elevated at 24 hr, suggesting an enhanced liver energy status. In summary, we believe ketogenesis is stimulated by major trauma. Initially, the gut supports ketone concentration in the systemic circulation, whereas, by 24 hr, the gut becomes a ketone consumer and the liver maintains circulating levels.

Abdominal Injuries↗

PubMed1991

Primed neutrophils injure rat lung through a platelet-activating factor-dependent mechanism.

Bacterial lipopolysaccharide (LPS) promotes transient lung neutrophil sequestration. These LPS-primed neutrophils, when stimulated by an N-formyl peptide (FNLP), promote lung injury. We hypothesized that LPS-primed, FNLP-stimulated neutrophils promote lung injury through a platelet-activating factor (PAF)-dependent mechanism. Rats were pretreated with either saline or WEB2170, a PAF receptor antagonist (10 mg/kg po). One hour after pretreatment, rats were administered intraperitoneal LPS (salmonella typhimurium lipopolysaccharide, 500 micrograms/kg) followed 6 hr later by intravenous FNLP (250 micrograms/kg infused over 30 min). Two hours after the initiation of FNLP infusion, rats were sacrificed and assays were performed to measure: (1) lung neutrophil sequestration with myeloperoxidase (MPO) activity; (2) circulating neutrophil activation with nitroblue tetrazolium (NBT) staining, and (3) lung microvascular leak with 125I-albumin flux. We found that lung myeloperoxidase, circulating neutrophil NBT staining, and lung 125I-albumin flux were increased (P less than 0.05) in saline-pretreated LPS/FNLP rats, relative to control. While lung MPO remained increased (P less than 0.05) in WEB2170-pretreated LPS/FNLP rats, circulating neutrophil NBT and lung 125I-albumin flux were decreased (P less than 0.05) relative to those in saline-pretreated rats. We conclude that PAF mediates LPS/FNLP-induced neutrophil activation and lung injury, but is independent from lung neutrophil sequestration. Thus, lung neutrophil sequestration does not inevitably produce lung injury. Rather, neutrophils can accumulate in the lung without causing lung injury if neutrophil activation can be blocked.

Animals↗

PubMed1991

FNLP injures endotoxin-primed rat lung by neutrophil-dependent and -independent mechanisms.

Bacterial lipopolysaccharide (LPS) and an N-formyl peptide, N-formyl-neoleucyl-leucyl-phenylalanine (FNLP), synergistically promote lung injury in rats as measured by 125I-labeled albumin flux. Concomitantly, neutrophils are sequestered in the lung. We hypothesized that LPS-FNLP-induced lung injury is mediated both by neutrophil-dependent and -independent mechanisms. Rats were depleted of circulating and marginating neutrophils with vinblastine. LPS-FNLP-induced lung protein leak was partially decreased in these neutrophil-depleted animals, although a component of lung injury remained. We hypothesized that LPS-FNLP-induced lung injury was also mediated by xanthine oxidase (XO). Rats were fed a tungsten-enriched diet that inactivates molybdenum-dependent oxidase systems. LPS-FNLP-induced lung leak was partially decreased in these animals as well. When tungsten-fed rats were also neutrophil depleted with vinblastine, no increase in 125I-albumin flux was observed in response to LPS-FNLP. In parallel experiments, lungs from vinblastine-pretreated rats were isolated and perfused. FNLP infusion into the LPS-primed, crystalloid-perfused lungs caused increased 125I-albumin flux, which was prevented by oxidase inhibition. We conclude that LPS-FNLP-induced lung injury is both neutrophil mediated and neutrophil independent. The nonneutrophil component of the LPS-FNLP-induced lung injury appears to be pulmonary XO derived and dependent.

Animals↗