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W R Summer

Publications and source records attributed to W R Summer.

At least 37 records · Page 2Linked to original sources
PubMed1998

Enhancement of peritoneal leukocyte function by granulocyte colony-stimulating factor in rats with abdominal sepsis.

OBJECTIVE: To investigate the therapeutic effects of granulocyte colony-stimulating factor (G-CSF) on the functional activities of circulating and peritoneal neutrophils during intra-abdominal sepsis. DESIGN: Placebo, controlled study, using a rat model of intra-abdominal sepsis. SETTING: Animal research facility. SUBJECTS: Male specific pathogen-free Sprague-Dawley rats. INTERVENTIONS: Abdominal sepsis was produced in rats by cecal ligation and puncture. The control animals received a sham operation. G-CSF (subcutaneous injection at 50 microg/kg) or vehicle (100 microL of 5% dextrose) treatment was initiated at 1 hr after cecal ligation and puncture or sham operation and repeated at 12-hr intervals thereafter. MEASUREMENTS AND MAIN RESULTS: Six hours after cecal ligation and puncture, CD11b/c and CD18 expression on circulating neutrophils was significantly up-regulated when compared with those in the sham operated control animals. Peritoneal neutrophils exhibited a further up-regulation of these adhesion molecules than did the circulating neutrophils. A sustained up-regulation of CD11b/c and CD18 was found in peritoneal neutrophils even at 24 hrs after cecal ligation and puncture. G-CSF treatment increased CD11b/c expression on circulating neutrophils in 6-hr sham-operated rats, but did not further up-regulate CD11b/c or CD18 expression on circulating or peritoneal neutrophils in cecal ligation and puncture rats. Phagocytic activities of circulating neutrophils assessed by uptake of fluorescent latex microspheres were lower in 24-hr cecal ligation and puncture rats when compared with the sham-operated controls. G-CSF treatment prevented this inhibition. Furthermore, G-CSF enhanced the phagocytic activities of peritoneal neutrophils in both 6- and 24-hr cecal ligation and puncture rats when compared with those of the vehicle-treated animals. Spontaneous hydrogen peroxide generation by circulating neutrophils was increased in 6-hr cecal ligation and puncture rats, but not in 24-hr cecal ligation and puncture rats. Peritoneal neutrophils exhibited an inhibition of phorbol myristate acetate-stimulated hydrogen peroxide generation. G-CSF treatment did not up-regulate neutrophil hydrogen peroxide generation. CONCLUSIONS: Circulating and peritoneal neutrophils exhibit marked polymorphism in their functional activities during the host response to abdominal sepsis. G-CSF treatment significantly enhanced the phagocytic function of both circulating and peritoneal neutrophils which may be one mechanism underlying its protective effect in abdominal sepsis.

Abdomen↗
PubMed1998

Fluorescein-labeled dextran concentration is increased in BAL fluid after ANTU-induced edema in rats.

Several methodologies have been developed to assess alveolocapillary membrane permeability in acute lung injury. The purpose of this study was to determine the reliability of FITC-dextran compared with radioactive tracers to assess lung permeability alterations. After intraperitoneal administration of alpha-naphthylthiourea (ANTU, 50 mg/kg) or DMSO-ANTU vehicle, the animals were euthanized and their lungs were studied in an isolated-lung preparation. FITC-dextran or radiolabeled tracers were added to the perfusate. At 2 h the bronchoalveolar lavage (BAL) fluid from the ANTU group showed a significantly greater amount of fluorescence in the supernatant after centrifugation of BAL fluid compared with the DMSO group. Consistent results were observed with the radioactive tracers: there was an increase in extravascular albumin space and extravascular lung water compared with the control group. No cleavage of the FITC from the dextran molecule was evident by chromatography comparing samples recovered from the BAL fluid to the pure FITC-dextran molecule. In conclusion, measurement of FITC-dextran in the supernatant of BAL fluid after intravascular administration is a reliable method of assessing lung permeability changes in vivo and ex vivo.

Animals↗
PubMed1998

Acute ethanol intoxication inhibits neutrophil beta2-integrin expression in rats during endotoxemia.

The effects of acute ethanol intoxication on neutrophil [polymorphonuclear leukocyte (PMN)] adhesion molecule expression and certain other functional properties during endotoxemia were studied in rats to elucidate the mechanisms underlying the immunosuppressive effects of ethanol. Acute ethanol intoxication was induced by an intraperitoneal injection of 20% ethanol at a dose of 5.5 g of ethanol/kg. Control animals received an intraperitoneal injection of saline. Thirty minutes after intraperitoneal injection, animals were given a 90-min intravenous infusion of Escherichia coli endotoxin (total dose of 112.5 microg/rat in 2.5 ml of saline) or saline. Certain rats received granulocyte colony-stimulating factor (G-CSF; 50 microg/kg in 5% dextrose, subcutaneous injection twice daily) or vehicle pretreatment for 2 days before intravenous endotoxin infusion. Endotoxemia significantly upregulated CD11b/c and CD18 expression on PMNs when compared with those of saline-infused rats. Acute ethanol intoxication inhibited this endotoxin-induced upregulation of CD11b/c and CD18 expression on PMNs. Ethanol intoxication also suppressed the phagocytic activities of PMNs in saline-infused rats, but this suppression failed to reach statistical significance in endotoxin-infused rats. Hydrogen peroxide generation by PMNs in saline- or endotoxin-infused rats was not affected by ethanol intoxication. Histological examination showed extensive PMN sequestration in the liver after endotoxin infusion, and ethanol intoxication significantly attenuated this hepatic sequestration of PMNs. G-CSF pretreatment enhanced neutrophil phagocytosis, CD11b/c and CD18 expression in endotoxin-infused rats, and prevented the ethanol-induced inhibition of neutrophil CD18 expression and phagocytosis. The impairment of beta2-integrin expression on PMNs may be one mechanism underlying ethanol-induced defects of neutrophil delivery into tissue sites of infection. G-CSF may be of benefit to the infected alcoholic host by enhancing leukocyte defense functions.

Alcoholic Intoxication↗
PubMed1998

Adenoviral-mediated interferon-gamma gene therapy augments pulmonary host defense of ethanol-treated rats.

Alcohol has long been recognized as an immunosuppressive drug and a risk factor for a spectrum of infectious diseases. Among these infections, bacterial pneumonias are most closely correlated with alcohol abuse. One potential mechanism of ethanol-induced immunosuppression is through its ability to suppress alveolar macrophage production of tumor necrosis factor (TNF-alpha). This defect can be reversed by priming macrophages with interferon-gamma (IFN-gamma). We hypothesized that macrophage priming in vivo in a model of acute ethanol intoxication could augment pulmonary host defenses. To test this hypothesis, we used adenoviral-mediated gene transfer of the IFN-gamma gene. This strategy resulted in prolonged expression of IFN-gamma in vivo. Moreover, in a model of acute ethanol intoxication, this vector significantly enhanced lipopolysaccharide-induced TNF-alpha responses and lung polymorphonuclear leukocyte recruitment. Furthermore, pulmonary host defenses against Klebsiella pneumoniae were significantly augmented. These enhanced host defenses were not reversed with pretreatment with a polyclonal anti-TNF-alpha antibody, suggesting that IFN-gamma's effect was through a non-TNF-alpha-dependent mechanism. These data demonstrate that ethanol-induced suppression of pulmonary host defenses can be reversed with IFN-gamma gene therapy.

Adenoviridae↗
PubMed1997

The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group.

BACKGROUND: In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases, but the pathophysiologic role of these prostaglandins is unclear. In animal models, inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival. In pilot studies of patients with sepsis, treatment with ibuprofen led to improvements in gas exchange and airway mechanics. METHODS: From October 1989 to March 1995, we conducted a randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (10 mg per kilogram of body weight [maximal dose, 800 mg], given every six hours for eight doses) in 455 patients who had sepsis, defined as fever, tachycardia, tachypnea, and acute failure of at least one organ system. RESULTS: In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis. With ibuprofen therapy there was no increased incidence of renal dysfunction, gastrointestinal bleeding, or other adverse events. However, treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days (mortality, 37 percent with ibuprofen vs 40 percent with placebo). CONCLUSIONS: In patients with sepsis, treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever, tachycardia, oxygen consumption, and lactic acidosis, but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival.

Acidosis, Lactic↗
PubMed1997

Phase 1 safety trial of Filgrastim (r-metHuG-CSF) in non-neutropenic patients with severe community-acquired pneumonia.

The objectives of the present study were to: (1) evaluate the safety of Filgrastim therapy in non-neutropenic patients with severe community-acquired pneumonia; (2) determine the absolute neutrophil count (ANC) response to various dosages of Filgrastim in non-neutropenic patients with active infection; and (3) describe the impact of therapy with Filgrastim in combination with antibiotics on selected pneumonia-related clinical parameters. The study design was an open-label, dose-ranging, clinical trial, set in the General Clinical Research Unit of a large, public community hospital. The study population consisted of 30 patients who had presented to the Emergency Department with severe, community-acquired pneumonia. One of five dosages (75, 150, 300, 450 or 600 micrograms day-1) of Filgrastim (r-metHuG-CSF) was given subcutaneously daily for 10 days, until discharge or until the absolute neutrophil count > 75 x 10(9) l(-1), whichever was earlier. Vital signs, pulse oximetry, arterial blood gases, daily complete blood counts with differential, serum chemistries, coagulation profiles, electrocardiograms, chest radiographs, plasma G-CSF concentrations and duration of hospitalization were measured. There was no evidence of Filgrastim-related lung injury or evidence of extra-pulmonary toxicity. There was no apparent dose-response effect of Filgrastim on pneumonia-related clinical variables. Dosages of Filgrastim between 150 and 600 micrograms day-1 had similar effects on increasing the ANC. Filgrastim appeared to be safe in non-neutropenic patients with severe, community-acquired pneumonia when given in dosages of 75-600 micrograms day-1 in combination with appropriate antibiotic therapy. Further study is needed to determine the effect of Filgrastim on morbidity, mortality and duration of symptoms in this patient population.

Adult↗
PubMed1997

Intraportal lipopolysaccharide suppresses pulmonary antibacterial defense mechanisms.

Translocation of enteric bacteria or their components (or both) has been postulated to play a role in precipitating sepsis or the systemic inflammatory response syndrome. To simulate the effects of translocation on pulmonary host defenses, lipopolysaccharide was injected into the portal vein of normal rats that were subsequently challenged by aerosol inoculation with Pseudomonas aeruginosa. Injection of LPS into the portal vein resulted in increased serum tumor necrosis factor (TNF)-alpha levels and reduction in lung clearance of P. aeruginosa after aerosol challenge. There were corresponding reductions in alveolar neutrophil recruitment, diminished alveolar macrophage phagocytosis and superoxide anion (O2-) production, and diminished lung TNF recovered by bronchoalveolar lavage. Furthermore, prior intravenous injection of recombinant TNF-alpha reproduced the defective bacterial clearance, the altered recruitment of airspace neutrophils, and the defective alveolar macrophage phagocytosis. Thus, systemic TNF-alpha is important in altering pulmonary defenses, and this work supports the concept that bacterial translocation may adversely affect host defenses in distant organs.

Animals↗
PubMed1997

Modulation of the lung host response by granulocyte colony-stimulating factor in rats challenged with intrapulmonary endotoxin.

The effects of granulocyte colony-stimulating factor (G-CSF) on the functional activities of circulating and lung-recruited neutrophils (PMNs) and alveolar macrophages (AMs) were studied in rats to further elucidate the mechanisms underlying G-CSF-enhanced pulmonary host defense. Animals received G-CSF or vehicle twice a day for 2 days, followed by an intratracheal challenge with endotoxin or saline. G-CSF up-regulated CD11b/c expression and mean channel fluorescence intensity of phagocytosis in circulating PMNs. G-CSF also enhanced phagocytic activities, reflected by both the percentage of phagocytosis and mean channel fluorescence intensity in lung-recruited PMNs and AMs in intratracheal endotoxin-challenged rats. The endotoxin-induced increase in pulmonary production of tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant was not affected by G-CSF pretreatment. These data demonstrate that G-CSF-enhanced pulmonary recruitment of PMNs is primarily based on the effects of G-CSF on the PMNs themselves, rather than the generation of certain chemotactic stimuli, i.e., cytokine-induced neutrophil chemoattractant and tumor necrosis factor-alpha. The enhanced phagocytic activities of lung-recruited PMNs and AMs also augment pulmonary host defenses in G-CSF-pretreated animals.

Animals↗
PubMed1997

Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs.

Keratinocyte growth factor (KGF) prevents alpha-naphthylthiourea (ANTU)-induced permeability edema ex vivo. To explore the mechanisms in this involved effect, we administered KGF (5 mg/kg, intratracheally) 48 h prior to ANTU (50 mg/kg, intraperitoneally). Several groups were studied: phosphate-buffered saline/dimethylsulfoxide (PBS/DMSO) (vehicles), PBS/ANTU, and KGF/ANTU. At 90 min after ANTU injection the lungs were removed, ventilated, and perfused ex vivo for 180 min. Quantification of fluorescein isothiocyanate (FITC)-labeled dextran in bronchoalveolar lavage fluid (BALF) was used to assess alveolar capillary barrier permeability. KGF attenuated ANTU-induced edema and blockade of sodium transport, with ouabain (10(-3) M) or amiloride (10(-4) M) added ex vivo reversed this effect. FITC-dextran was increased in the PBS/ANTU group as compared with the PBS/DMSO group, indicating permeability edema. In the KGF/ANTU group, there was concentration of BALF FITC-dextran, consistent with permeability edema and increased alveolar fluid export. Albumin space measurements showed similar increases in permeability in the PBS/ANTU and KGF/ANTU groups. Extravascular lung water (measured with radiolabeled erythrocytes) was decreased in the KGF/ANTU group. Following KGF pretreatment, uninjured lungs exported more intratracheal PBS than normal lungs following terbutaline stimulation ex vivo. In conclusion, KGF, through type II alveolar pneumocyte hyperplasia with increased sodium-potassium-adenosine triphosphatase (Na,K-ATPase) activity, attenuated ANTU-induced edema formation by potentiating alveolar fluid clearance.

Absorption↗
PubMed1997

Exacerbation of murine Pneumocystis carinii infection by adenoviral-mediated gene transfer of a TNF inhibitor.

The role of mononuclear phagocytes and their cytokine products in host defense against Pneumocystis carinii (PC) remains unclear. The cytokine tumor necrosis factor (TNF) has been proposed as critical for host defense against this pathogen. To investigate the role of this cytokine in PC infection, we treated immunocompetent mice (CD4+) or mice depleted of CD4 lymphocytes (CD4-) with a recombinant adenovirus encoding a TNF inhibitor gene (AdTNF-R). AdTNF-R treated CD4+ animals displayed delayed clearance of PC after intratracheal inoculation, whereas AdTNF-R treated CD4 animals developed more severe chronic infection. Moreover, AdTNF-R treated CD4- animals, in contrast to control CD4- mice, failed to show any interleukin-6 (IL-6) gene induction in the lung after PC challenge. The results firmly implicate TNF in host defense against PC, and support a role for TNF in orchestrating the intrapulmonary cytokine cascade in PC infection.

Adenoviridae↗
PubMed1997

Venous thromboembolism. A contemporary diagnostic and therapeutic approach.

Patients with risk factors for VTE and developing signs or symptoms remotely consistent with DVT or PE should undergo formal testing. Ultrasound and IPG have good sensitivity and specificity in symptomatic DVT. V/Q lung scans should be obtained in all patients with suspected PE or proven DVT. A prior clinical assessment of probability, based on risk factors, history, physical examination, chest film, and arterial blood gas analysis, can aid in the interpretation of V/Q scans. Normal scans exclude PE. High-probability scans confirm PE if the clinical probability is at least intermediate. Nondiagnostic scans are common, but diagnosis in such cases can be aided by noninvasive leg studies. Heparin therapy should be started when there is suspicion of VTE. To avoid recurrence, a therapeutic aPTT of 1.5 to 2.5 times the control rate should be achieved as soon as possible after the diagnosis of VTE is confirmed. Thrombolytics are reserved for hemodynamically compromised patients. Warfarin should be administered to achieve an INR of 2.0 to 3.0 and should be continued for at least 3 months in patients with low risk of recurrence and probably for at least 6 months in all other patients.

Anticoagulants↗
PubMed1997

Acute ethanol intoxication suppresses the pulmonary inflammatory response in rats challenged with intrapulmonary endotoxin.

The effects of acute ethanol intoxication on the functional activities of circulating and lung-recruited polymorphonuclear leukocytes (PMNs) and alveolar macrophages (AMs) were determined in rats challenged with intratracheal endotoxin to elucidate the mechanisms underlying the defects of pulmonary host defenses caused by acute ethanol intoxication. Acute ethanol Intoxication was induced by an intraperitoneal injection of 20% ethanol at a dose of 5.5 g of ethanol/kg. The control animals were injected with an equal amount of saline. Thirty min after intraperitoneal injection, rats were challenged with intratracheal endotoxin (300 micrograms/kg in 0.5 ml of saline) or saline. The rats were killed 3 h after intratracheal injection. CD11b/c expression on PMNs and phagocytosis and hydrogen peroxide generation of PMNs and AMs were determined by flow cytometry. Cytokine-Induced neutrophil chemoattractant (CINC) level in bronchoalveolar lavage fluid was measured with a specific ELISA. Intratracheal endotoxin caused a significant PMN recruitment into the lung in control animals. Acute ethanol intoxication completely suppressed the endotoxin-induced pulmonary recruitment of PMNs. Pulmonary-recruited PMNs exhibited a significant upregulation (8-fold) of CD11b/c expression when compared with circulating PMNs. This upregulation of CD11b/c expression was abolished by ethanol intoxication. Ethanol intoxication suppressed hydrogen peroxide generation by AMs and lung-recruited PMNs, and the phagocytosis of circulating PMNs. In contrast, acute ethanol intoxication did not affect pulmonary CINC production. These data indicate that the antiinflammatory effects of alcohol seem to be primarily based on the effects of ethanol on the PMNs themselves and not on the generation of certain chemotactic stimuli. In addition to the impairment of PMN recruitment, the suppression of AM and PMN activities also contributes to the mechanisms underlying ethanol-induced defects of pulmonary host defenses.

Alcoholic Intoxication↗
PubMed1996

Use of transient CD4 lymphocyte depletion to prolong transgene expression of E1-deleted adenoviral vectors.

E1-deleted adenoviral vectors are increasingly being utilized for in vivo gene transfer. The potential use of these vectors is limited by transient expression of the transgene and a markedly reduced rate of transduction following readministration, presumably due to a host immune response to the vector. We hypothesized that CD4+ lymphocytes are necessary to generate an immune response to these vectors and that administration of a depleting anti-CD4 antibody (GK1.5) might prolong transgene expression in vivo. We found that pretreatment of mice with a single injection (transient depletion) or weekly injections of GK1.5 (persistent depletion), markedly prolonged expression of an adenovirus-encoded tumor necrosis factor (TNF) inhibitor or luciferase gene compared to controls. Moreover, mice treated with GK1.5 showed no antiadenoviral antibody response to repeat administration of the vector and a second adenoviral transgene could be expressed in these animals. However, control mice developed a significant neutralizing antibody response that prevented transgene expression with administration of a second adenovirus. These findings demonstrate that manipulation of the host immune response may expand potential applications of gene transfer utilizing adenoviral vectors.

Adenovirus E1 Proteins↗
PubMed1996

Acute respiratory failure in pregnancy.

Pregnancy increases the risk for respiratory failure from to numerous pulmonary diseases. Adult respiratory distress syndrome, aspiration, venous air embolism, asthma, thromboembolism, and heart disease are etiologies shared by non-pregnant women. However, their management is complicated by complex physiologic changes during pregnancy. Amniotic fluid embolism and tocolytic-induced pulmonary edema are unique to pregnancy and must be added to the list of causes of respiratory failure. Diagnostics and supportive care is difficult and must be directed with the mother and the fetus in mind. This dictates a thorough understanding of maternal physiology, and the safety of drug use during pregnancy.

Acute Disease↗
PubMed1996

Keratinocyte growth factor attenuates lung leak induced by alpha-naphthylthiourea in rats.

OBJECTIVE: To investigate the effect of pretreatment with keratinocyte growth factor on acute permeability pulmonary edema. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Specific pathogen-free Sprague-Dawley rats. INTERVENTION: Acute permeability pulmonary edema was induced with an injection of alpha-naphthylthiourea, and lung leak was assessed in an isolated perfused lung model over 180 mins. Leak was confirmed with wet/dry lung weight ratios, and the alveolar fluid protein concentration was measured after bronchoalveolar lavage. The effect of pretreatment with keratinocyte growth factor (injected intratracheally 48 hrs before the experiment) on alpha-naphthylthiourea-induced pulmonary edema was assessed (keratinocyte growth factor/alpha-naphthylthiourea group). Control groups (Control and keratinocyte growth factor/Control) were also studied. Histopathology was performed for each of the four groups. MEASUREMENTS AND MAIN RESULTS: The alpha-naphthylthiourea produced an acute permeability pulmonary edema detected by lung leak over the 180-min ex vivo period of monitoring the isolated perfused lung (leak = 8+/-mL; wet/dry weight ratio 14.7+/-2; lavage protein 3.1+/-1 mg/mL). Pretreatment with keratinocyte growth factor significantly attenuated these parameters (leak = 2.3+/-0.4 mL; wet/dry weight ratio 7.1 +/- 0.5; lavage protein 0.28 +/-0.03 mg/mL), which were not significantly different from the control group and the keratinocyte growth factor/control group. Histopathology showed abundant type II pneumocyte hyperplasia in the lungs of animals pretreated with keratinocyte growth factor, and marked pulmonary edema in animals pretreated with alpha-naphthylthiourea. Less edema was apparent in the keratinocyte growth factor/alpha-naphthylthiourea group. All data are expressed as mean +/- SEM. CONCLUSIONS: Pretreatment with keratinocyte growth factor significantly attenuates pulmonary edema induced by alpha-naphthylthiourea. The mechanisms of this protection are likely related to type II pneumocyte hyperplasia, but remain to be specifically elucidated.

Animals↗
PubMed1996

Alcohol modulates alveolar macrophage tumor necrosis factor-alpha, superoxide anion, and nitric oxide secretion in the rat.

We investigated the effect of alcohol (ethanol) on the ability of the alveolar macrophage to produce tumor necrosis factor-alpha (TNF-alpha), superoxide anion (O2-), and nitric oxide (NO)--three critical components of pulmonary host defense. Male rats were treated with alcohol either acutely (priming dose 175 mg/100 g of body weight, followed by a 7-hr continuous intravenous infusion of 30 mg/100 g of body weight/hr) or chronically (12-14 weeks of feeding ethanol in a liquid diet). Three hours before sacrifice, the rats received an intravenous injection of saline or lipopolysaccharide (LPS; Escherichia coli, 026:B6, 100 micrograms/100 g of body weight). Alveolar macrophages (AMs) were then isolated by bronchoalveolar lavage and assessed for their in vitro capacity to produce TNF-alpha, O2-, and NO spontaneously and in response to different stimuli. Acute alcohol administration suppressed in vitro LPS-stimulated AM TNF-alpha secretion by 52%. AMs from both pair-and alcohol-fed rats secreted TNF-alpha spontaneously in culture. However, the AMs from chronic alcohol-fed group secreted 42-53% less TNF-alpha spontaneously and in response to LPS, interferon-gamma (IFN-gamma) or IFN-gamma + LPS compared with the AMs from pair-fed group. Systemic LPS treatment inhibited in vitro LPS-stimulated AM TNF-alpha secretion (50%) only in the control rats. Acute alcohol administration enhanced significantly in vitro phorbol 12-myristate 13-acetate (PMA)- and opsonized zymosan (OPZ)-induced AM O2- secretion (4-and 1.8-fold, respectively). Systemic LPS treatment primed the AMs from control rats to secrete 83% more O2- in response to PMA but not OPZ; however, in the acute alcohol-treated group, it suppressed both PMA (54%)- and OPZ (66%)-induced AM O2- release (loss of priming effect of LPS). Chronic alcohol feeding suppressed PMA-induced AM O2- secretion (40%) without affecting the OPZ-induced release. Although systemic LPS treatment had no significant effect on PMA or OPZ-induced AM O2- secretion in the pair-fed group, it enhanced the PMA-stimulated AM O2- release (88%) in the alcohol-fed group. AMs recovered from control or acute alcohol-treated rats did not secrete NO spontaneously in vitro. However, AMs from both pair and chronic alcohol-fed rats secreted NO spontaneously with AMs from chronic alcohol-fed group secreting 34% less. Both acute and chronic alcohol treatment inhibited AM NO secretion in response to IFN-gamma, LPS, and IFN-gamma + LPS significantly. Systemic LPS had no effect on AM NO production in response to different in vitro stimuli in any of the treatment groups. These data suggest that (1) both acute and chronic alcohol administration to rats inhibit AM TNF-alpha and NO secretion; (2) acute and chronic alcohol treatment have differential effects on AM O2- secretion; and (3) alcohol-induced alteration in AM TNF-alpha, O2-, and NO secretion may in part explain the increased susceptibility of alcohol-consuming individuals to pulmonary infections.

Alcoholic Intoxication↗
PubMed1995

Adenovirus-mediated blockade of tumor necrosis factor in mice protects against endotoxic shock yet impairs pulmonary host defense.

A replication-deficient recombinant adenovirus encoding a chimeric protein capable of binding tumor necrosis factor (TNF) and lymphotoxin was given to mice. Administration of this virus (10(9) pfu intravenously) yielded high levels of the recombinant protein in plasma and afforded significant protection to a lethal challenge with lipopolysaccharide with or without D-galactosamine. However, this protein inhibitor was readily detectable in the lung and was associated with decreased neutrophil recruitment and bacterial killing after intratracheal LPS or Pseudomonas aeruginosa, respectively. These data reflect the dual role of many proinflammatory cytokines. This model of TNF inhibition is similar to the homozygous 55-kDa TNF receptor deletion; thus, adenovirus-mediated gene transfer of cytokine inhibitors in vivo is a useful tool to abrogate the function of single or multiple cytokines for investigational or therapeutic purposes.

Adenoviridae↗