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1.
Med Mal Infect ; 39(12): 871-6, 2009 Dec.
Article in French | MEDLINE | ID: mdl-19875257

ABSTRACT

Doripenem is a new member of the carbapenem family. Its spectrum is a little wider than meropenem and it is active on some Pseudomonas aeruginosa strains resistant to other carbapenems and on Burkholderia cepacia. Doripenem was evaluated in nosocomial pneumonia including ventilator-acquired pneumonia, complicated intra-abdominal infection, and complicated urinary tract infection. In nosocomial pneumonia, doripenem showed an interesting activity in P. aeruginosa infected patients. This data, along with the global increase in multiresistance, may be an opportunity to optimize our therapeutic options with a new molecule.


Subject(s)
Anti-Bacterial Agents , Carbapenems , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/economics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Burkholderia cepacia/drug effects , Carbapenems/adverse effects , Carbapenems/chemistry , Carbapenems/economics , Carbapenems/pharmacology , Carbapenems/therapeutic use , Clinical Trials as Topic , Cross Infection/drug therapy , Doripenem , Drug Evaluation, Preclinical , Drug Resistance, Multiple, Bacterial , Humans , Nervous System Diseases/chemically induced , Peritonitis/drug therapy , Pneumonia, Bacterial/drug therapy , Pseudomonas aeruginosa/drug effects , Urinary Tract Infections/drug therapy
2.
Clin Vaccine Immunol ; 15(12): 1868-77, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18971303

ABSTRACT

Antibodies against Saccharomyces cerevisiae mannan (ASCA) and antibodies against synthetic disaccharide fragments of glucans (ALCA) and chitin (ACCA) are biomarkers of Crohn's disease (CD). We previously showed that Candida albicans infection generates ASCA. Here, we explored ALCA and ACCA as possible biomarkers of invasive C. albicans infection (ICI). ASCA, ALCA, ACCA, and Candida mannan antigen and antibody detection tests were performed on 69 sera obtained sequentially from 18 patients with ICIs proven by blood culture, 59 sera from CD patients, 47 sera from hospitalized subjects colonized by Candida species (CZ), and 131 sera from healthy controls (HC). ASCA, ALCA, and ACCA levels in CD and ICI patients were significantly different from those in CZ and HC subjects (P<0.0001). In ICI patients, these levels increased as infection developed. Using ASCA, ALCA, ACCA, and Platelia Candida tests, 100% of ICIs were detected, with the kinetics of the antibody response depending on the patient during the time course of infection. A large number of sera presented with more than three positive tests. This is the first evidence that the detection of antibodies against chitin and glucans has diagnostic value in fungal infections and that these tests can complement more specific tests. Future trials are necessary to assess the value of these tests in multiparametric analysis, as well as their pathophysiological relevance.


Subject(s)
Antibodies, Fungal/blood , Candida albicans , Candidiasis/diagnosis , Chitin/immunology , Glucans/immunology , Mannans/immunology , Saccharomyces cerevisiae/immunology , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Candidiasis/immunology , Crohn Disease/immunology , Female , Humans , Male , Middle Aged , Retrospective Studies
3.
Clin Microbiol Infect ; 14(4): 337-43, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18190582

ABSTRACT

Respiratory isolates of Pseudomonas aeruginosa were collected from 58 critically-ill patients with ventilator-associated pneumonia. Expression of elastase and pyocyanin was assessed semi-quantitatively, while quorum-sensing activity was assessed by quantifying the levels of the autoinducers N-3-oxododecanoyl-L-homoserine lactone (C12-HSL) and N-butanoyl-L-homoserine lactone (C4-HSL). Correlations were sought between quorum-sensing activity and the expression of these two virulence factors, and all results were compared to those obtained with the laboratory reference strains PA103, a strain defective in quorum-sensing, and PAO1, a functional quorum-sensing strain. More than two-thirds of clinically pathogenic isolates had increased levels of elastase and/or pyocyanin, and high quorum-sensing activity, as assessed by autoinducer levels. However, a strong correlation between quorum-sensing activity and virulence factor production was revealed only for elastase and not for pyocyanin (C12-HSL/elastase, r = 0.7, p 2 x 10(-9); C4-HSL/elastase, r = 0.7, p 2 x 10(-9)). These data suggest that the pathogenicity of P. aeruginosa isolates from critically-ill patients with ventilator-associated pneumonia is caused, at least in part, by an increase in elastase production regulated by quorum-sensing, while increased pyocyanin production in these isolates may be regulated predominantly by mechanisms other than quorum-sensing.


Subject(s)
Gene Expression Regulation, Bacterial , Pneumonia, Ventilator-Associated/microbiology , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/pathogenicity , Quorum Sensing , Virulence Factors/metabolism , 4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/metabolism , Bacterial Proteins , Humans , Pancreatic Elastase/genetics , Pancreatic Elastase/metabolism , Pseudomonas aeruginosa/growth & development , Pseudomonas aeruginosa/isolation & purification , Pyocyanine/genetics , Pyocyanine/metabolism , Virulence Factors/genetics
4.
Eur Respir J ; 30(1): 31-9, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17392324

ABSTRACT

Chronic allergic asthma is associated with marked inflammatory reaction, microvascular leakage and epithelium injury. As previously shown in a rat model of chronic asthma, these alterations increase lung permeability and distal airway fluid clearance. Keratinocyte growth factor (KGF) has been shown to induce epithelial cell proliferation and to protect from acute lung injuries. Therefore, the current authors evaluated the potential role of KGF treatment on lung permeability and airway inflammation in rats with chronic asthma. KGF (1 mg x kg(-1)) was administered intravenously before the last ovalbumin (OVA) challenge in sensitised rats. Permeability was assessed by the leak of radiolabelled albumin from the alveolar and systemic compartments. Histopathological analysis was also performed. Treatment with KGF decreased the leak of both markers and decreased the level of extravascular lung water in sensitised rats challenged with OVA. KGF treatment also reduced the inflammatory cell number in bronchoalveolar lavage fluid but not in bronchial mucosa. KGF markedly limited the allergen-induced alterations in epithelium integrity and the expression of the intercellular junction proteins beta-catenin and zonula occludens protein-1. In conclusion, keratinocyte growth factor administration markedly limits lung permeability and airway inflammation, an effect associated with a decrease in epithelium alterations during chronic allergic asthma. These data open new prospects in the therapeutic strategy of asthma.


Subject(s)
Bronchi/metabolism , Epithelium/metabolism , Fibroblast Growth Factor 7/metabolism , Lung/pathology , Animals , Asthma/metabolism , Epithelial Cells/metabolism , Hypersensitivity , Inflammation , Lung/metabolism , Male , Mucous Membrane/metabolism , Ovalbumin/metabolism , Permeability , Rats , beta Catenin/metabolism
5.
Infect Immun ; 73(7): 4263-71, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15972518

ABSTRACT

The type III secretion system (TTSS) is a specialized cytotoxin-translocating apparatus of gram-negative bacteria which is involved in lung injury, septic shock, and a poor patient outcome. Recent studies have attributed these effects mainly to the ExoU effector protein. However, few studies have focused on the ExoU-independent pathogenicity of the TTSS. For the present study, we compared the pathogenicities of two strains of Pseudomonas aeruginosa in a murine model of acute lung injury. We compared the CHA strain, which has a functional TTSS producing ExoS and ExoT but not ExoU, to an isogenic mutant with an inactivated exsA gene, CHA-D1, which does not express the TTSS at all. Rats challenged with CHA had significantly increased lung injury, as assessed by the wet/dry weight ratio for the lungs and the protein level in bronchoalveolar lavage fluid (BALF) at 12 h, compared to those challenged with CHA-D1. Consistent with these findings, the CHA strain was associated with increased in vitro cytotoxicity on A549 cells, as assessed by the release of lactate dehydrogenase. CHA was also associated at 12 h with a major decrease in polymorphonuclear neutrophils in BALF, with a proinflammatory response, as assessed by the amounts of tumor necrosis factor alpha and interleukin-1beta, and with decreased bacterial clearance from the lungs, ultimately leading to an increased mortality rate. These results demonstrate that the TTSS has a major role in P. aeruginosa pathogenicity independent of the role of ExoU. This report underscores the crucial roles of ExoS and ExoT or other TTSS-related virulence factors in addition to ExoU.


Subject(s)
Cytotoxins/metabolism , Pseudomonas aeruginosa/pathogenicity , Pulmonary Alveoli/microbiology , Virulence Factors/metabolism , Animals , Cell Line , Humans , Interleukin-10/biosynthesis , Lung/pathology , Neutrophils/physiology , Protein Transport , Pseudomonas Infections/mortality , Pseudomonas aeruginosa/metabolism , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/biosynthesis
6.
Clin Exp Immunol ; 132(1): 61-9, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12653837

ABSTRACT

Activation of leucocytes during airway inflammatory reaction involves adhesion to bronchial epithelial cells (BEC), a process implicating specific interactions between glycoproteins with epithelial cell surface proteins, mainly intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In this study, the effect of keratinocyte growth factor (KGF), a growth factor involved in pulmonary epithelium repair, was evaluated on adhesion molecule expression with BEAS-2B cells and BEC and granulocyte adherence to BEAS-2B. The modulation by KGF of membrane and mRNA expression of ICAM-1 and VCAM-1 was studied on confluent cells stimulated or not with tumour necrosis factor-alpha (TNF) (200 UI/ml) or TNF and interleukin (IL)-4 (50 UI/ml and 10 ng/ml). Levels of soluble-(s)ICAM-1 and sVCAM-1 were measured by ELISA. Although moderately, KGF significantly decreased membrane ICAM-1 expression in unstimulated BEAS-2B cells (24% inhibition at 100 ng/ml) or in TNF- or TNF + IL-4-stimulated cells (22.5 and 18.7% inhibition, respectively). Treatment with KGF tended to decrease VCAM-1 expression in TNF- and TNF + IL-4-stimulated BEAS-2B (P = n.s. and P < 0.05, 14 and 15% inhibition, respectively). In primary culture of BEC, adhesion molecule expression was also reduced. ICAM-1 and VCAM-1 mRNA expression were also inhibited by KGF. Levels of sICAM-1 and sVCAM-1 were not significantly increased in supernatants from KGF-treated cells (30% and 24% increase at 100 ng/ml, respectively) compared to controls. Moreover, KGF decreased by 31% the adherence of neutrophils to TNF-activated BEAS-2B. In conclusion, KGF decreases ICAM-1 and VCAM-1 expression and neutrophil adherence in BEC. These suggest its involvement in the resolution of the inflammatory reaction.


Subject(s)
Bronchi/immunology , Epithelial Cells/immunology , Fibroblast Growth Factors/pharmacology , Intercellular Adhesion Molecule-1/analysis , Vascular Cell Adhesion Molecule-1/analysis , Cell Adhesion/drug effects , Cell Line , Epithelial Cells/drug effects , Fibroblast Growth Factor 7 , Flow Cytometry , Humans , Intercellular Adhesion Molecule-1/genetics , Interleukin-4/pharmacology , Neutrophils/cytology , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Statistics, Nonparametric , Tumor Necrosis Factor-alpha/pharmacology , Vascular Cell Adhesion Molecule-1/genetics
7.
Am J Physiol Heart Circ Physiol ; 280(3): H1311-7, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11179078

ABSTRACT

Hydrostatic pulmonary edema is a common complication of congestive heart failure, resulting in substantial morbidity and mortality. Keratinocyte growth factor (KGF) is a mitogen for type II alveolar epithelial and microvascular cells. We utilized the isolated perfused rat lung model to produce hydrostatic pulmonary edema by varying the left atrial and pulmonary capillary pressure. Pretreatment with KGF attenuated hydrostatic edema formation. This was demonstrated by lower wet-to-dry lung weight ratios, histological evidence of less alveolar edema formation, and reduced alveolar accumulation of intravascularly administered FITC-labeled large-molecular-weight dextran in rats pretreated with KGF. Thus KGF attenuates injury in this ex vivo model of hydrostatic pulmonary edema via mechanisms that prevent increases in alveolar-capillary permeability.


Subject(s)
Fibroblast Growth Factors/pharmacology , Fluorescein-5-isothiocyanate/analogs & derivatives , Pulmonary Alveoli/physiopathology , Pulmonary Edema/drug therapy , Pulmonary Edema/physiopathology , Animals , Blood Pressure , Capillaries/physiology , Capillary Permeability/drug effects , Capillary Permeability/physiology , Dextrans/pharmacokinetics , Fibroblast Growth Factor 7 , Fluorescein-5-isothiocyanate/pharmacokinetics , Hydrostatic Pressure , In Vitro Techniques , Male , Organ Size , Perfusion , Pulmonary Alveoli/blood supply , Pulmonary Alveoli/pathology , Pulmonary Circulation/physiology , Pulmonary Edema/pathology , Rats , Rats, Sprague-Dawley , Specific Pathogen-Free Organisms
8.
Am J Physiol Lung Cell Mol Physiol ; 279(6): L1199-209, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11076810

ABSTRACT

We have previously reported that keratinocyte growth factor (KGF) attenuates alpha-naphthylthiourea-induced lung injury by upregulating alveolar fluid transport. The objective of this study was to determine the effect of KGF pretreatment in Pseudomonas aeruginosa pneumonia. A 5% bovine albumin solution with 1 microCi of (125)I-labeled human albumin was instilled into the air spaces 4 or 24 h after intratracheal instillation of P. aeruginosa, and the concentration of unlabeled and labeled proteins in the distal air spaces over 1 h was used as an index of net alveolar fluid clearance. Alveolocapillary barrier permeability was evaluated with an intravascular injection of 1 microCi of (131)I-albumin. In early pneumonia, KGF increased lung liquid clearance (LLC) compared with that in nonpretreated animals. In late pneumonia, LLC was significantly reduced in the absence of KGF but increased above the control value with KGF. KGF pretreatment increased the number of polymorphonuclear cells recovered in the bronchoalveolar lavage fluid and decreased bacterial pulmonary translocation. In conclusion, KGF restores normal alveolar epithelial fluid transport during the acute phase of P. aeruginosa pneumonia and LLC in early and late pneumonia. Host response is also improved as shown by the increase in the alveolar cellular response and the decrease in pulmonary translocation of bacteria.


Subject(s)
Fibroblast Growth Factors , Growth Substances/pharmacology , Pneumonia, Bacterial/drug therapy , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa , Albumins/pharmacokinetics , Animals , Body Fluids/metabolism , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/microbiology , Disease Models, Animal , Fibroblast Growth Factor 10 , Fibroblast Growth Factor 7 , Iodine Radioisotopes , Macrophages, Alveolar/immunology , Macrophages, Alveolar/microbiology , Pneumonia, Bacterial/mortality , Pneumonia, Bacterial/pathology , Pseudomonas Infections/mortality , Pseudomonas Infections/pathology , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/microbiology , Pulmonary Alveoli/pathology , Rats , Rats, Sprague-Dawley , Specific Pathogen-Free Organisms , Survival Rate
9.
Crit Care Med ; 27(3): 576-82, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10199539

ABSTRACT

OBJECTIVE: Multiwavelength near infrared (NIR) spectrophotometry can monitor the redox state of cytochrome a,a3 (cyt a,a3) in vivo. Because cyt a,a3 is the most immediate reductant of oxygen, this technique has been proposed to evaluate tissue oxygenation. The purpose of this study was to examine the relationship between cyt a,a3 oxidation level as an indicator of dysoxia and oxygen uptake (VO2) when oxygen delivery (DO2) was progressively lowered in an in situ vascularly isolated hindlimb. DESIGN: Prospective, randomized, laboratory study. SETTING: University research laboratory. SUBJECTS: Fourteen pigs. INTERVENTIONS: Measurement of critical values for both VO2 and cyt a,a3 oxidation during ischemic and hypoxic hypoxia. MEASUREMENTS AND MAIN RESULTS: The right hindlimb of anesthetized, paralyzed, and ventilated pigs was subjected to progressive ischemic or hypoxic hypoxia for 100 mins by ten stepwise decreases in DO2. In ischemic hypoxia (n = 7), arterial inflow (Q) from a pump-membrane oxygenator system was lowered from 50 to 0 mL/min, with PaO2 maintained at 100 mm Hg. In hypoxic hypoxia (n = 6), PaO2 was lowered from 100 mm Hg to 0 mm Hg. Hindlimb DO2 was calculated as the product of Q and arterial oxygen content, and VO2 as the product of Q and arteriovenous difference. The cyt a,a3 oxidation level was measured every 10 secs with a four-wavelength spectrophotometer. These parameters were measured 9 mins after each change of DO2. Critical values for both VO2 and cyt a,a3 oxidation level as a function of DO2 were determined in each animal by dual linear regression analysis. In ischemic and hypoxic hypoxia, a strong correlation was found between cyt a,a3 oxidation level and VO2 in both ischemic and hypoxic hypoxia (r2 =.90 and .87, respectively). Hindlimb vascular resistance increased in ischemic hypoxia and decreased in hypoxic hypoxia when DO2 reached critical DO2. CONCLUSIONS: From these results, we concluded that monitoring the cyt a,a3 redox state by NIR spectrophotometry is, in this experimental setting, a sensitive indicator of dysoxia during regional hypoxic or ischemic hypoxia.


Subject(s)
Electron Transport Complex IV/metabolism , Hemodynamics , Hindlimb/blood supply , Hypoxia/metabolism , Oxygen Consumption , Animals , Hypoxia/diagnosis , Hypoxia/enzymology , Ischemia/metabolism , Linear Models , Muscle, Skeletal/metabolism , Oxidation-Reduction , Random Allocation , Spectroscopy, Near-Infrared , Swine
10.
J Appl Physiol (1985) ; 85(3): 842-8, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9729556

ABSTRACT

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.


Subject(s)
Bronchoalveolar Lavage Fluid/chemistry , Dextrans/pharmacokinetics , Edema/metabolism , Fluorescein-5-isothiocyanate/analogs & derivatives , Animals , Capillary Permeability/physiology , Cell Count , Edema/chemically induced , Erythrocytes/metabolism , Fluorescein-5-isothiocyanate/pharmacokinetics , Injections, Intraperitoneal , Injections, Intravenous , Lung/metabolism , Pulmonary Circulation , Rats , Serum Albumin/metabolism , Thiourea/analogs & derivatives
11.
J Crit Care ; 13(2): 58-66, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9627272

ABSTRACT

PURPOSE: The aim of this study was to assess the respective role of a small elevation in pulmonary capillary pressure, airway pressure, or both on alveolar capillary barrier permeability in an isolated perfused rat lung model. MATERIALS AND METHODS: Four groups were studied with low or high airway pressure (LA: 10 mL/kg (tidal volume); HA: 20 mL/kg), low or high pulmonary artery pressure (LP: 9 mm Hg; HP: 12 mm Hg): LALP, HALP, LAHP, and HAHP. The lungs were ventilated and perfused ex vivo for 30 minutes. Quantification of fluorescein isothiocyanate-labeled (FITC) dextran in bronchoalveolar lavage (BAL) fluid and radiolabeled tracers assessed alveolar capillary barrier permeability. RESULTS: BALF FITC-dextran was similar in the three groups with either one or two low-pressure parameters (LALP, LAHP, HALP), but high amounts were found in the HAHP group (375.2 x 10(-6) mg/mL v, respectively, 21.4, 26.2, and 30 x 10(-6) mg/mL, P = .0001). These results were consistent with the albumin space and extravascular lung water: higher values only in the HAHP group statistically different from the other groups (P < .002). Interalveolar pore examined with scanning electron microscopy showed an increase in diameters between LALP and HAHP (P < .0001). CONCLUSIONS: We can conclude that elevation of either the pulmonary artery pressure from 8 to 11 mm Hg or the alveolar pressure from 10 to 15 mm Hg alone does not change the permeability of the alveolar capillary membrane; however, there is an additive effect of these pressures.


Subject(s)
Air Pressure , Barotrauma/physiopathology , Blood-Air Barrier/physiology , Lung Injury , Positive-Pressure Respiration , Pulmonary Wedge Pressure/physiology , Respiratory Distress Syndrome/physiopathology , Animals , Barotrauma/pathology , Capillary Permeability/physiology , Extravascular Lung Water/physiology , Lung/pathology , Lung/physiopathology , Microcirculation/pathology , Microcirculation/physiopathology , Microscopy, Electron, Scanning , Perfusion , Pulmonary Alveoli/blood supply , Pulmonary Alveoli/pathology , Rats , Respiratory Distress Syndrome/blood , Tidal Volume/physiology
15.
Am J Respir Crit Care Med ; 155(5): 1777-84, 1997 May.
Article in English | MEDLINE | ID: mdl-9154891

ABSTRACT

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.


Subject(s)
Fibroblast Growth Factors , Growth Substances/pharmacology , Pulmonary Alveoli/metabolism , Pulmonary Edema/metabolism , Sodium/metabolism , Absorption , Amiloride/pharmacology , Animals , Biological Transport , Bronchoalveolar Lavage Fluid/chemistry , Capillary Permeability , Dimethyl Sulfoxide/pharmacology , Enzyme Activation , Extravascular Lung Water/metabolism , Fibroblast Growth Factor 10 , Fibroblast Growth Factor 7 , Ouabain/pharmacology , Pulmonary Alveoli/pathology , Pulmonary Edema/chemically induced , Pulmonary Edema/pathology , Pulmonary Edema/physiopathology , Rats , Sodium Chloride , Sodium-Potassium-Exchanging ATPase/metabolism , Thiourea/analogs & derivatives
16.
Crit Care Med ; 24(6): 925-31, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8681593

ABSTRACT

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.


Subject(s)
Fibroblast Growth Factors , Growth Substances/therapeutic use , Pulmonary Edema/prevention & control , Rodenticides/antagonists & inhibitors , Thiourea/analogs & derivatives , Animals , Bronchoalveolar Lavage Fluid/chemistry , Fibroblast Growth Factor 10 , Fibroblast Growth Factor 7 , Growth Substances/administration & dosage , Organ Size/drug effects , Prospective Studies , Pulmonary Edema/chemically induced , Pulmonary Edema/pathology , Pulmonary Wedge Pressure , Random Allocation , Rats , Rats, Sprague-Dawley , Thiourea/antagonists & inhibitors
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