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Biomedical subjects

W R Summer

Publications and source records attributed to W R Summer.

At least 91 records · Page 5Linked to original sources
PubMed1989

Compartmentalization of intraalveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflammatory response.

Tumor necrosis factor-alpha (TNF), a monokine produced by lipopolysaccharide (LPS)-stimulated macrophages, is an activator of phagocytic functions and may modulate host responses during infection. To determine the effects of LPS on TNF activity and the pulmonary inflammatory response in vivo, we challenged rats systemically or intratracheally with LPS. Intravenous LPS significantly increased serum TNF content from nondetectable levels in control specimens to peak levels at 90 min, which declined to baseline by 3 h. In response to intratracheal LPS, levels of TNF both in bronchoalveolar lavage fluid and associated with alveolar macrophages increased significantly from near nondetectable levels in control animals. Increases in TNF levels were confined to the LPS-challenged compartment. Intravenous LPS resulted in a decrease in the number of peripheral blood neutrophils and in sequestration of these cells within the pulmonary vasculature. In contrast, intratracheal LPS elicited a marked intraalveolar inflammatory response.

Animals↗
PubMed1989

The effects of acute and chronic alcoholism on tumor necrosis factor and the inflammatory response.

Ethanol intoxication has been shown to suppress selected functions of the immune system, thereby compromising host defenses against bacterial infections. Because the macrophage secretory protein, tumor necrosis factor (TNF), plays a central role in the inflammatory cascade, the effect of acute and chronic alcoholism on lipopolysaccharide (LPS)-induced TNF activity was studied. Saline or ethanol was given intraperitoneally to normal or chronic alcoholic rats followed 30 min later by either intravenous or intratracheal LPS. Intravenous LPS caused a substantial increase in serum TNF at 90 min in both normal and chronic alcoholic rats. In marked contrast, peak serum TNF levels were significantly suppressed in normal and chronic alcoholic rats given an acute injection of ethanol. When LPS was instilled intratracheally into normal rats, high levels of TNF appeared in the bronchoalveolar lavage fluid. Similar levels of TNF were found in chronic alcoholic rats after intratracheal LPS. However, acute ethanol intoxication significantly inhibited LPS-induced TNF in bronchoalveolar lavage fluid. In a similar manner, acute ethanol intoxication, but not chronic alcohol consumption, markedly inhibited both systemic and intrapulmonary polymorphonuclear leukocyte aggregation in response to either intravenous or intratracheal LPS. Alcohol-induced inhibition of TNF is a potential mechanism of the antiinflammatory effects of ethanol.

Alcoholic Intoxication↗
PubMed1989

Right ventricular performance after monocrotaline-induced pulmonary hypertension.

Chronic pulmonary hypertension leads to a compensatory hypertrophy of the right ventricle (RV). Performance of the hypertrophied heart has been shown to vary depending on the type and severity of the overload, the species, age, and sex of the animal in which the hypertrophy is induced and the ventricle to which the overload is applied (left ventricle vs. right ventricle). In this study we employed two novel approaches to examine the performance of the hypertrophied right ventricle in male Sprague-Dawley rats. First, monocrotaline (MCT), a pyrrolizidine alkaloid isolated from the plant Crotalaria spectabilis, was used to noninvasively induce chronic pulmonary hypertension, RV pressure overload, and RV hypertrophy. After 5 wk the RV-to-(left ventricle + septum) ratio was increased by 94% over control. The volume of isolated right ventricular myocytes from MCT-treated rats was increased due primarily to an increase in cell cross-sectional area. Second, a stable, isolated, working heart preparation, normally used to study left ventricular function, was modified to study right ventricular function. In vitro ventricular performance of severely hypertrophied hearts was elevated compared with control hearts at all preloads. Significant elevations in positive and negative maximum pressure development (dP/dtmax) suggested that both the rate of pressure development and the rate of relaxation were enhanced. Coronary flow and RV-diastolic pressure were similar in the MCT and control group. Thus RV hypertrophy caused by a chronic pressure overload induced by MCT resulted in enhanced ventricular performance with no evidence of failure.

Animals↗
PubMed1989

Endothelin produces pulmonary vasoconstriction and systemic vasodilation.

Endothelin is a newly described polypeptide derived from endothelial cells. The effects of porcine endothelin on the pulmonary vascular bed and systemic vascular bed were investigated in the anesthetized, intact-chest cat under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of porcine endothelin (100-1000 ng) produced a mild vasoconstrictor response in the pulmonary vascular bed. The pulmonary vasoconstrictor response to endothelin was not altered when pulmonary vasomotor tone was increased by infusion of U46619. In contrast to this mild pulmonary vasoconstrictor response, endothelin decreased systemic arterial pressure. Moreover, injections of porcine endothelin into the right and left atria produced similar reductions in aortic pressure as well as similar increases in cardiac output and decreases in systemic vascular resistance. The systemic vasodilator response to porcine endothelin was not affected by beta 2-adrenoceptor blockade. The present data suggest that endothelin does not undergo significant first-pass pulmonary metabolism. The pulmonary vasoconstrictor response to bolus injections of porcine endothelin is not altered by changes in pulmonary vasomotor tone. In contrast, endothelin markedly dilated the systemic vascular bed independently of activation of beta 2-adrenoceptors. The present study provides the first report of the activity of endothelin on pulmonary and systemic hemodynamics in vivo. Moreover, the potent vasodilator activity of endothelin in the systemic vascular bed and its weak effect on pulmonary vessels suggest that endothelin may be more important in the regulation of peripheral vasomotor tone than the pulmonary vascular bed.

Adrenergic beta-Antagonists↗
PubMed1989

[Contribution of experimental models to the treatment of respiratory tract infections].

The need for more effective and potentially less toxic antimicrobial agents than aminoglycosides for treatment of gram negative bacilli pneumonia specially Pseudomonas aeruginosa, explains the interest for experimental models of pneumonia. These models allow to study the efficacy and safety of antibiotics alone or in combination. Aminoglycosides and new quinolones are more effective than beta-lactams for life threatening infection with high inoculum, the only exception to this finding has been for N-formimidoyl thienamycin, whereas for less severe infections aminoglycosides and beta-lactams are equivalent in efficacy. In contrast to high inocula pneumonia, combining beta-lactams with aminoglycosides give additive of synergic benefits for treating low inocula. Experimental models allow to compare continuous versus intermittent administration of antibiotics, different regimens of the same antibiotics (single daily dose of aminoglycosides versus conventional administration) and new antiinfectious agents as anti-pseudomonas hyperimmune globulins.

4-Quinolones↗
PubMed1988

'GABA shift' in vivo: enhancement of benzodiazepine binding in vivo by modulation of endogenous GABA.

The enhancement of benzodiazepine binding by gamma-aminobutyric acid (GABA) and its analogues has been described in detail in brain membrane preparations, but results in in vivo preparations such as tissue slices or animals treated with GABA modulators are conflicting. This 'GABA shift' in vitro has been reported for compounds with agonist effects at the benzodiazepine receptor but not for antagonists. We examined the effects of modulators of endogenous GABA on benzodiazepine receptor binding in vivo as determined by specific uptake of the benzodiazepine antagonist [3H]Ro 15-1788. Enhancement of radioligand uptake was observed in cortex, hypothalamus, hippocampus and pons-medulla 4 h after treatment with aminooxyacetic acid (AOAA), in cortex, cerebellum, hypothalamus, hippocampus and pons-medulla 0.5 h after treatment with valproic acid, and in cortex, cerebellum, hypothalamus and hippocampus 6 h after treatment with gamma-vinyl-GABA. GABA concentrations were increased at each of these points, as were synaptosomal GABA concentrations in prior studies. In contrast, no changes in radioligand uptake or GABA concentrations were observed 12 and 24 h after gamma-vinyl-GABA treatment. Increases in binding appeared to be due to increased apparent affinity at the receptor rather than a change in receptor number. These data indicate that binding of a benzodiazepine antagonist undergoes a GABA shift in vivo analogous to that observed with agonists in vitro.

Aminooxyacetic Acid↗
PubMed1988

Inotropic interactions of dichloroacetate with amrinone and ouabain in isolated hearts from endotoxin-shocked rats.

The inotropic effects of ouabain and amrinone singly and in combination with dichloroacetate (DCA) were assessed using isolated working perfused hearts from endotoxin-shocked (LD50/6 h) rats, with glucose and free fatty acids as substrates. Amrinone (2.7 X 10(-4) M) and ouabain (10(-5) M) alone improved myocardial mechanical performance from 25 to 75%, depending on the preload. Amrinone was more effective than ouabain at all left atrial filling pressures tested. DCA enhanced the inotropic effect of both compounds, improving myocardial work greater than 65% in combination with ouabain (at low filling pressures) to 125% with amrinone (at high filling pressures). Glucose oxidation rose two- to threefold when DCA was present with either drug. Ouabain was without effect on pyruvate dehydrogenase (PDH) activity; however, when present with DCA, PDH activity increased fourfold. Amrinone alone augmented PDH activity 2.5 times as compared with controls, and 4.5 times when combined with DCA. All three compounds individually elevated myocardial ATP levels, but in contrast to the inotropic effects, when used in combination caused no further increase in ATP. Myocardial cyclic AMP (cyclic AMP) levels were augmented five times control values in the presence of amrinone. The simultaneous presence of DCA and amrinone did not further augment the myocardial concentration of cAMP. DCA alone enhanced the myocardial oxidation of glucose in isolated myocardial cells from endotoxin-shocked animals. In contrast, ouabain and amrinone did not affect cellular glucose oxidation. These data indicate that the provision of DCA can enhance the inotropic effect of amrinone and ouabain on the isolated working heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1988

The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury.

Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compared an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 microM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 microM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 microM). To produce lung injury, t-bu-OOH (300 microM) was infused throughout the first minute of 4 successive 10-min periods.(ABSTRACT TRUNCATED AT 250 WORDS)

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1988

Endotoxin-induced suppression of pulmonary antibacterial defenses against Staphylococcus aureus.

In order to evaluate the effect of endotoxin on lung host defenses, Sprague-Dawley rats were intravenously injected with either placebo or 5 mg/kg of Escherichia coli lipopolysaccharide B. Two hours after treatment, animals were challenged with Staphylococcus aureus by either low dose aerosol inhalation or high dose intratracheal instillation of the bacteria into the lungs. Quantitative lung bacteriologic examination and bronchoalveolar lavage (BAL) for total and differential cell counts were performed immediately (zero hour) and at 4 h after bacterial challenge. Lung phagocytic defenses against aerosolized S. aureus challenges are provided solely by the alveolar macrophage (AM) in the absence of inflammation. In aerosol-challenged control rats, 20.6 +/- 2.0% of the initial deposited bacterial challenge remained viable in the lung at 4 h. Animals pretreated with endotoxin, however, showed a significant decrease in pulmonary bactericidal activity (31.3 +/- 3.4% bacteria remaining at 4 h), indicating a defect in alveolar macrophage (AM) function. Further assessment of the bactericidal oxidative metabolism of endotoxin-treated AM by luminol-enhanced chemiluminescence indicated an increased production of free radical oxygen species when compared with control nontreated cells in both the unstimulated (66 +/- 4 versus 38 +/- 7 x 10(3) cpm in control) and stimulated (250.5 +/- 17.1 versus 147.1 +/- 6.2 x 10(3) cpm in control) states. Total and differential cell counts in both control and endotoxin-treated aerosol-challenged rats were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1988

Peripheral type benzodiazepine receptor and airway smooth muscle relaxation.

It has been postulated that a benzodiazepine receptor with a micromolar affinity may be associated with Ca++ channels in peripheral organs. We examined the actions of Ro5-4684 (parachlorodiazepam) and midazolam on guinea pig tracheal smooth muscle contraction. Binding studies using [3H]Ro5-4684 indicate the presence of a "peripheral" type binding site with a Kd of approximately 4 nM and maximum binding of 1 pmol/mg of protein. Midazolam did not displace radioligand. In tension studies no activity was seen for Ro5-4684 or midazolam at concentrations below 1 microM. Higher concentrations relaxed the airway smooth muscle under basal tone, the effect was augmented significantly by epithelium removal. Similar results were obtained in tissues precontracted with methacholine or KCl. Midazolam (1 or 100 microM) significantly (P less than .05) attenuated the response to Ca++ in K+-depolarized tracheal strips, the effect was greater at low Ca++ concentrations. The compounds appear to function as Ca++ antagonists in airway smooth muscle but ar not typical as shown by their ability to reduce basal tone in airway smooth muscle.

Animals↗
PubMed1988

Chronic benzodiazepine administration. II. Discontinuation syndrome is associated with upregulation of gamma-aminobutyric acidA receptor complex binding and function.

A "withdrawal" or "rebound" syndrome may follow the abrupt discontinuation of chronic treatment with benzodiazepines. To assess the neurochemical basis of this syndrome, mice were treated with lorazepam, 2 mg/kg/day for 7 days, a course which produces tolerance and downregulation of receptor binding and function. Behavioral studies indicated that open-field activity in lorazepam-treated mice was similar to controls at 1 day postlorazepam. Activity was increased at 4 days postlorazepam, and had returned to control levels by day 7. Benzodiazepine receptor binding as measured by specific uptake of [3H]Ro15-1788 in several brain regions returned to control levels by day 2 postbrazepam but had increased above controls at day 4 postlorazepam. Binding returned to control levels by day 7. Similar results were observed using [3H]flunitrazepam in membrane preparations. A similar time course was also observed for the maximum binding of the chloride channel ligand t-[35S]butylbicyclophosphorothionate during this period. The IC50 value for muscimol inhibition of t-butylbicyclophosphorothionate binding was decreased at day 4, suggesting increased coupling between gamma-aminobutyric acid and the chloride channel. Muscimol-stimulated [36Cl-] up-take in cortical synaptoneurosomes was increased at day 4 postlorazepam. These results indicate that the benzodiazepine discontinuation syndrome is associated with upregulation of receptor binding and function at the gamma-aminobutyric acidA receptor complex.

Animals↗
PubMed1987

Neoplastic superior vena caval obstruction: diagnosis with percutaneous needle aspiration.

Obstruction of the superior vena cava arises from a spectrum of etiologies that include both benign and malignant conditions. Therefore, management of this serious disorder varies and depends on the underlying cause. Pursuit of a histologic diagnosis with invasive procedures has been associated with a wide range of diagnostic yields and complications. Percutaneous fine-needle aspiration biopsy has been shown to be highly reliable and well tolerated in the diagnosis of a variety of mediastinal and lung masses. Three patients are presented with obstruction of the superior vena cava in whom computed tomography safely guided percutaneous needle biopsy in obtaining a correct histologic diagnosis. It appears that transthoracic percutaneous needle aspiration biopsy is safe and efficacious in patients with superior vena cava syndrome, but further experience with this increasingly available procedure is warranted.

Aged↗
PubMed1987

Erythromycin-induced suppression of pulmonary antibacterial defenses. A potential mechanism of superinfection in the lung.

Erythromycin is a broad-spectrum antibiotic commonly used in patients with respiratory infections. Certain of these patients become colonized with new microorganisms and develop superinfections. Antibiotics have a number of effects other than simply killing or inhibiting the growth of bacteria and may have direct effects upon host cells, including phagocytes. In vitro and in vivo studies have demonstrated that erythromycin decreases polymorphonuclear leukocyte (PMN) directed migration. To test the hypothesis that erythromycin inhibits normal PMN migration into the alveoli in response to a bacterial challenge, mice were challenged by aerosol inhalation with Proteus mirabilis or Staphylococcus aureus and injected intravenously with erythromycin (50 or 100 mg/kg). Pulmonary bactericidal activity and total lavaged lung cell and differential counts were determined 4 h after bacterial challenge. In control mice, only 24 +/- 2% of the initial inoculum of P. mirabilis was viable at 4 h. At a dose of 100 mg/kg, lung defenses after erythromycin were ablated, allowing the proliferation of P. mirabilis to 113 +/- 5% of the initial inoculum. The number of PMN obtained by lavage after P. mirabilis challenge was also inhibited by erythromycin in a dose-dependent manner. In untreated animals, 5.0 +/- 0.2 x 10(6) PMN were recovered as compared with 3.1 +/- 0.4 x 10(6) and 1.1 +/- 0.3 x 10(6) with increasing doses of erythromycin. Intrapulmonary bactericidal activity against S. aureus was not impaired by erythromycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Interactions of clindamycin with antibacterial defenses of the lung.

Clindamycin is speculated to have select advantages in the treatment of certain infections because biologically active antibiotic is internalized by macrophages and PMNs in vitro. By challenging pulmonary host defenses with various bacterial species as probes, we were able to evaluate clindamycin-phagocyte interaction in vivo. A murine model was developed using an implanted mini-osmotic pump to maintain constant clindamycin blood levels at 1/4 MIC (1 microgram/ml). Mice pretreated for 24 h with clindamycin killed a significantly greater percentage of intratracheally inoculated Bacteroides thetaiotaomicron in 4 h than did control animals (37 +/- 2% versus 7 +/- 5%). The enhancing effects of clindamycin on pulmonary defenses could not be duplicated by a 1-h preincubation of B. theta in 1/4 MIC of clindamycin before inoculation into untreated mice. Clindamycin blood levels of 1 microgram/ml did not alter the rate at which Pseudomonas aeruginosa (clindamycin-resistant) was killed by pulmonary defenses, suggesting that clindamycin did not cause nonspecific activation of phagocytic defenses. Both PMNs and alveolar macrophages lavaged from the lungs of clindamycin-treated mice contained bioassayable concentrated intracellular antibiotic. The presence of intracellular antibiotic was further supported by experiments in which the intrapulmonary killing of large numbers of Staphylococcus aureus (sensitive, but not resistant organisms) was significantly enhanced (89 +/- 5 versus 70 +/- 5%) by clindamycin pretreatment. In contrast, phagocytes lavaged from mice with constant 1/4 MIC (4 micrograms/ml) blood levels of penicillin G had no detectable intracellular antibiotic activity and did not augment the intrapulmonary killing of B. theta.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Granular cell tumour of the bronchus: bronchoscopic and clinical features.

Granular cell tumours are uncommon, generally benign neoplasms of uncertain origin that occasionally affect the tracheobronchial tree. Their incidence seems to be increasing, despite the fact that such tumours are rarely suspected on clinical grounds or bronchoscopic appearance. Here we describe three cases of endobronchial granular cell tumours, one of which regressed spontaneously after biopsy, and review previous accounts of their bronchoscopic and clinical features.

Bronchoscopy↗
PubMed1986

Characterization of the pulmonary inflammatory response to an anaerobic bacterial challenge.

Anaerobic bacteria from the oral flora are important causes of aspiration pneumonia and lung abscess. However, the pulmonary antibacterial response to these organisms has not been well described. To define this, mice were intratracheally inoculated with 10(9) Bacteroides gingivalis, a member of the B. melaninogenicus group, and a common clinical isolate from periodontal disease and anaerobic pulmonary infections. Studies after intratracheal challenge included bacteriologic and histopathologic examination, pulmonary cellular response, lactic dehydrogenase (LDH) and albumin levels in lung lavage fluid, and wet lung weight. Overall mortality was 25%. In the surviving animals, pulmonary lavage showed a marked recruitment of polymorphonuclear leukocytes that was associated with significant bacterial killing by 48 h. Histopathologic examination showed an acute, severe necrotizing bronchopneumonia. Pulmonary abscess formation occurred in 37% of animals. Severe parenchymal damage was further documented by a marked increase in LDH levels in lavage fluids. Mean LDH levels in lavage fluid increased to 850 +/- 25 units/first lavage at 24 h postchallenge compared with control values of 65 +/- 10 units/first lavage. Lung lavage also demonstrated an extensive influx of serum albumin consistent with injury to the alveolar capillary membrane. Albumin levels in lung lavage were highest at 24 h after intratracheal challenge (3.25 +/- 0.3 mg/first lavage), whereas lavage fluid from control mice had nondetectable albumin levels. Wet lung weights maximally increased from 0.12 +/- 0.01 g in control mice to 0.28 +/- 0.03 g 24 h after bacterial-challenge. These data demonstrate tht B. gingivalis causes marked inflammation in the lung that progresses to severe bronchopneumonia and lung abscess.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗