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Biomedical subjects

C Delclaux

Publications and source records attributed to C Delclaux.

At least 37 records · Page 2Linked to original sources
PubMed2000

No change of hyperleptinemia despite a decrease in insulin concentration in patients with chronic renal failure on a supplemented very low protein diet.

Chronic renal failure (CRF) is often accompanied by hyperleptinemia caused by deficient renal metabolism of leptin and possibly increased leptin production, which in turn may result from the hyperinsulinemia and increased proinflammatory cytokine levels in patients with CRF. The hyperinsulinemia and insulin resistance observed in patients with CRF improve on supplemented very low protein diets (SVLPDs). The goal of our study is to determine whether the correction of hyperinsulinemia and insulin resistance in patients with CRF by SVLPDs is accompanied by improvement in hyperleptinemia. Thirteen patients were studied before and 1 year after following SVLPDs providing 0.3 g/kg/d of protein, supplemented with amino acids and ketoanalogues. After 1 year, patients showed markedly less hyperinsulinemia (7.4 +/- 1.6 versus 13.8 +/- 2 microU/mL at the start of diet; P: = 0.05) and insulin resistance, whereas serum leptin levels remained unchanged (16.1 +/- 4.7 versus 19.1 +/- 7.4 ng/mL at start of the study; P: = not significant). The initial correlation between serum leptin level and percentage of body fat persisted during follow-up. No correlation was found between insulin and leptin levels or between the variation of these two parameters during the study. Our study shows that the correction of hyperinsulinemia and insulin resistance in patients with CRF by SVLPDs is not accompanied by improvement in hyperleptinemia, which consequently does not appear to result from changes in carbohydrate metabolism.

Dietary Proteins↗
PubMed2000

Multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome. Incidence, prognosis, and risk factors. ARDS Study Group.

We investigated the incidence, risk factors for, and outcome of ventilator-associated pneumonia (VAP) in patients with acute respiratory distress syndrome (ARDS). We compared 134 patients with ARDS with 744 patients without ARDS on mechanical ventilation. Fiberoptic bronchoscopic examination and quantitative bacterial cultures (protected brush or catheter sampling [threshold: 10(3) cfu/ml], or bronchoalveolar lavage [threshold: 10(4) cfu/ml]) were used to diagnose pneumonia. VAP occurred in 49 patients (36.5%). The incidence of pneumonia was 23% (173 of 744 patients) among patients without ARDS (p < 0.002). Nonfermenting gram-negative rods caused significantly more pneumonia in ARDS patients. Mortality rates were identical in ARDS patients with (28 of 49 patients, 57%) and without (50 of 85 patients, 59%) pulmonary infection (p = 0.8). VAP resulted in a considerable increase in attributable time on mechanical ventilation of both the overall population of ARDS patients and of survivors. Both the use of sucralfate (adjusted odds ratio [OR]: 4. 42; 95% confidence interval [CI]: 2.01 to 9.7, p = 0.0002) and the duration of exposure to sucralfate (adjusted OR: 1.206; 95% CI: 1. 095 to 1.328, p = 0.0002) were associated with an increased risk of VAP during ARDS. VAP considerably prolongs the time on mechanical ventilation without affecting survival. Patients given sucralfate may be at greater risk of developing pulmonary infection during ARDS.

Adult↗
PubMed2000

Hemodynamic tolerance of intermittent hemodialysis in critically ill patients: usefulness of practice guidelines.

Poor hemodynamic tolerance of intermittent hemodialysis (IHD) is a common problem for patients in an intensive care unit (ICU). New dialysis strategies have been adapted to chronic hemodialysis patients with cardiovascular insufficiency. To improve hemodynamic tolerance of IHD, specific guidelines were progressively implemented into practice through the year 1996 in our 26-bed medical ICU. To evaluate the efficiency of these guidelines we retrospectively compared all IHD performed during the years before (1995) and after (1997) implementation of these recommendations. Forty-five patients underwent 248 IHD sessions in 1995 and 76 patients underwent 289 IHD sessions in 1997. The two populations were similar for age, sex, chronic hemodialysis (26% versus 17%), and secondary acute renal failure. In 1997, patients were more severely ill with a higher SAPS II (50 +/- 17 versus 59 +/- 24; p = 0.036), and more patients required epinephrine or norepinephrine infusion before dialysis sessions (16% versus 34%; p < 0.0001). The compliance to guidelines was high, inducing a significant change in IHD modalities. As a result, hemodynamic tolerance was significantly better in 1997, with less systolic blood pressure drop at onset (33% versus 21%, p = 0. 002) and during the sessions (68% versus 56%, p = 0.002). IHD with hypotensive episode or need for therapeutic interventions were less frequent in 1997 (71% versus 61%, p = 0.015). The ICU mortality was similar (53.3% in 1995 versus 47.3% in 1997; p = 0.52) but death rate in 1997, but not in 1995, was significantly less than predicted from SAPS II (47.3% versus 65.6%; p = 0.02). Length of ICU stay was also reduced for survivors in 1997 (p = 0.04). Implementation of practice guidelines for intermittent hemodialysis in ICU patients lessens hemodynamic instability and may improve outcome.

Critical Illness↗
PubMed2000

Predictive value of pulmonary function parameters for sleep apnea syndrome.

Nocturnal polysomnography is the standard diagnostic test for sleep apnea syndrome (SAS) but is both expensive and time-consuming. We developed a predictive index for SAS based on pulmonary function data, including respiratory resistance determined by the forced oscillation technique, from 168 obese snorers with suspected SAS. Our model used logistic regression to obtain case-by-case predictions of the probability of SAS, defined as an apnea-hypopnea index (AHI) > or = 15 during overnight polysomnography. We then tested our model in a prospective group of 101 similar patients. Specific respiratory conductance and daytime oxygen saturation contributed significantly to the model. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the index computed from these parameters were 98%, 86%, 90%, and 97%, respectively. In the prospective group, the model proved repeatable, with 100% sensitivity, 84% specificity, 86% PPV, and 100% NPV. The high NPV may help to identify obese snorers with a SAS risk that is so low as to make polysomnography unnecessary. Based on the 50% prevalence of SAS in our study and on the fact that polysomnography is required in all patients with daytime somnolence, we calculated that using our model would have obviated the need for polysomnography in 38% of our patients.

Female↗
PubMed1999

Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study.

CONTEXT: Tumor necrosis factor alpha (TNF-alpha) is believed to be a cytokine central to pathogenesis of septic shock. TNF2, a polymorphism within the TNF-alpha gene promoter, has been associated with enhanced TNF-alpha production and negative outcome in some severe infections. OBJECTIVES: To investigate the frequency of the TNF2 allele in patients with septic shock and to determine whether the allele is associated with the occurrence and outcome of septic shock. DESIGN: Multicenter case-control study conducted from March 1996 to June 1997. SETTING: Seven medical intensive care units in university hospitals. SUBJECTS: Eighty-nine patients with septic shock and 87 healthy unrelated blood donors. MAIN OUTCOME MEASURES: Frequency of the TNF2 allele among patients with septic shock and among those who died and the level of corresponding TNF-alpha concentrations. RESULTS: Mortality among patients with septic shock was 54%, consistent with the predicted mortality from the Simplified Acute Physiologic Score (SAPS II) value. The polymorphism frequencies of the controls and the patients with septic shock differed only at the TNF2 allele (39% vs 18% in the septic shock and control groups, respectively, P =.002). Among the septic shock patients, TNF2 polymorphism frequency was significantly greater among those who had died (52% vs 24% in the survival group, P =.008). Concentrations of TNF-alpha were higher in 68% and 52% with the TNF2 and TNF1 polymorphisms, respectively, but their median values (48 pg/mL vs 29 pg/mL) were not statistically different (P = .31). After controlling for age and the probability of death, derived by the SAPS II score, multiple logistic regression analysis showed that, for the same rank of SAPS II value, patients with the TNF2 allele had a 3.7-fold risk of death (95% confidence interval, 1.37-10.24). CONCLUSION: The TNF2 allele is strongly associated with susceptibility to septic shock and death due to septic shock.

Alleles↗
PubMed1999

Outcome of nutritional status and body composition of uremic patients on a very low protein diet.

Concern has been raised about the nutritional adequacy of a very low protein diet (VLPD). Monthly clinical evaluation by a physician and dietitian and quarterly dietary records, anthropometric measurements, blood testing, and dual energy X-ray absorptiometry (DEXA) were used to assess the course of nutritional status for 1 year in 10 clinically stable patients (six men, four women; age, 57.1 +/- 9.3 years) with advanced chronic renal failure (mean glomerular filtration rate, 13.2 +/- 4.8 mL/min/1.73 m(2)). These patients received a VLPD providing 0.3 g/kg/d of protein and were supplemented with amino acids and ketoanalogues. Conventional nutritional markers remained unchanged after 1 year of the VLPD. However, during the same period, whole-body DEXA showed a significant decrease in lean tissue from 46.2 +/- 10.2 to 45.0 +/- 9. 8 kg (P < 0.02); limb-trunk lean tissue ratio was reduced from 0.86 +/- 0.12 to 0.82 +/- 0.12 (P < 0.02), total-body fat increased from 20.0 +/- 6.9 to 21.4 +/- 7.0 kg (P < 0.05), and the percentage of total-body fat increased from 29.2% +/- 8.7% to 31.7% +/- 8.8% (P < 0.03). These different modifications occurred abruptly during the first 3 months, then stabilized or slightly improved thereafter. These mild changes do not appear to be deleterious given the favorable long-term outcome of these patients, even after they began treatment by dialysis or after renal transplantation.

Absorptiometry, Photon↗
PubMed1999

Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in non-human immunodeficiency virus-infected patients: retrospective study of 31 patients.

The aim of this retrospective study was to assess whether corticosteroid adjunctive therapy (CAT) could prevent death in immunocompromised patients with severe Pneumocystis carinii pneumonia (PCP) who do not have human immunodeficiency virus (HIV) infection, similarly to what has been demonstrated for HIV-infected patients. The charts of all non-HIV-infected patients who were admitted to two medical intensive care units between 1988 and 1996 because of severe PCP, defined by an arterial oxygen pressure (determined while the patient was breathing room air) of <70 mm Hg, and who were treated with trimethoprim-sulfamethoxazole were analyzed retrospectively. Thirty-one patients met the study criteria, of whom 23 received CAT (within 72 hours of antibiotic therapy) and eight did not receive CAT. The need for mechanical ventilation (10 [43%] of 23 vs. 4 [50%] of 8) and the mortality rate (9 [39%] of 23 vs. 4 [50%] of 8) were similar for the two groups. Although this small study does not have a statistical power high enough to rule out the possibility of a difference, the results suggest that CAT does not improve the survival of non-HIV-infected patients as has been described for HIV-infected patients with severe PCP.

Adolescent↗
PubMed1998

Protective effect of endotoxin instillation on subsequent bacteria-induced acute lung injury in rats.

The phagocytic capability afforded by neutrophil influx into the lungs is essential to ward off invading bacteria. The objective of this study was to evaluate the effect of prior neutrophil recruitment induced by alveolar instillation of endotoxin (LPS, 200 micrograms/kg) 16 h before a pulmonary infection caused by instillation of live Pseudomonas aeruginosa ([PYO]: 1.5 x 10(8) colony-forming units [cfu]/kg) in rats. A first series of experiments showed that lipopolysaccharide (LPS) instillation induced recruitment of alveolar neutrophils that were capable, ex vivo, of elastase exocytosis, reactive oxygen species secretion, and PYO killing. In a second set of experiments, LPS followed by PYO was compared with PYO alone (n = 11 surviving rats in each group). Parameters were studied 24 h after the bacterial challenge. As compared with PYO alone, pretreatment with LPS followed by PYO was associated with decreased mortality (0% versus 54%, p < 0.05), decreased protein leakage into bronchoalveolar lavage (BAL) fluid (1.8 +/- 0.4 versus 13.5 +/- 2.2 mg/ml, p < 0.001), and improved bacterial clearance from BAL (4.0 +/- 1.4 x 10(2) versus 1.2 +/- 0.5 x 10(4) cfu/ml, p < 0.05) and from pulmonary parenchyma (8.5 +/- 6.4 x 10(5) versus 1.9 +/- 0.8 x 10(7) cfu/ml, p < 0.05). We conclude that prior alveolar endotoxin instillation induces local recruitment of functionally active neutrophils, and that this is associated with resistance to subsequent experimental pneumonia.

Animals↗
PubMed1998

Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS.

Because animal studies have demonstrated that mechanical ventilation at high volume and pressure can be deleterious to the lungs, limitation of airway pressure, allowing hypercapnia if necessary, is already used for ventilation of acute respiratory distress syndrome (ARDS). Whether a systematic and more drastic reduction is necessary is debatable. A multicenter randomized study was undertaken to compare a strategy aimed at limiting the end-inspiratory plateau pressure to 25 cm H2O, using tidal volume (VT) below 10 ml/kg of body weight, versus a more conventional ventilatory approach (with regard to current practice) using VT at 10 ml/kg or above and close to normal PaCO2. Both arms used a similar level of positive end-expiratory pressure. A total of 116 patients with ARDS and no organ failure other than the lung were enrolled over 32 mo in 25 centers. The two groups were similar at inclusion. Patients in the two arms were ventilated with different VT (7.1 +/- 1.3 versus 10.3 +/- 1.7 ml/kg at Day 1, p < 0.001) and plateau pressures (25.7 +/- 5. 0 versus 31.7 +/- 6.6 cm H2O at Day 1, p < 0.001), resulting in different PaCO2 (59.5 +/- 15.0 versus 41.3 +/- 7.6 mm Hg, p < 0.001) and pH (7.28 +/- 0.09 versus 7.4 +/- 0.09, p < 0.001), but a similar level of oxygenation. The new approach did not reduce mortality at Day 60 (46.6% versus 37.9% in control subjects, p = 0.38), the duration of mechanical ventilation (23.1 +/- 20.2 versus 21.4 +/- 16. 3 d, p = 0.85), the incidence of pneumothorax (14% versus 12%, p = 0. 78), or the secondary occurrence of multiple organ failure (41% versus 41%, p = 1). We conclude that no benefit could be observed with reduced VT titrated to reach plateau pressures around 25 cm H2O compared with a more conventional approach in which normocapnia was achieved with plateau pressures already below 35 cm H2O.

Adolescent↗
PubMed1998

Cell-matrix interactions modulate 92-kD gelatinase expression by human bronchial epithelial cells.

We have previously reported that primary human bronchial epithelial cells (HBECs) cultured on types I + III collagen were able to differentially regulate the production of major constitutive 92-kD gelatinase, minor 72-kD gelatinase, and their tissue-specific inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) in response to lipopolysaccharide (LPS) or proinflammatory cytokines, suggesting that HBECs may be involved in vivo in the active remodeling of the underlying extracellular matrix (ECM). In this study, we examined the possible effects of specific type IV collagen as compared with types I + III collagen on HBEC behavior and function. We investigated 92-kD gelatinase and TIMP-1 expression with zymography and reverse zymography, respectively, at the protein level, and with quantitative reverse transcription-polymerase chain reaction (RT-PCR) at the mRNA level. Results showed similar morphologic features and identical proliferation rates of HBECs in response to the two matrix substrates. Nevertheless, differences at the protein and mRNA levels between HBEC cultures on type IV collagen and on types I + III collagen included: (1) a lower basal level of 92-kD gelatinase production; (2) less upregulation of 92-kD gelatinase in response to LPS endotoxin or to the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha); and (3) loss of activation of the proforms of the 92-kD and 72-kD gelatinases. These findings, together with the maintenance of TIMP-1 expression, strongly suggest that type IV collagen used as a matrix substratum is associated with a homeostatic HBEC phenotype, and limits the ability of HBECs to degrade the matrix. In contrast, types I + III collagen may be associated with a matrix resorption phenotype corresponding to active matrix remodeling and repair. Thus, the ECM underlying HBECs may modulate matrix remodeling by HBECs, particularly in response to inflammatory processes during acute lung injury.

Bronchi↗
PubMed1997

Acute bacterial pneumonia in rats increases alveolar epithelial fluid clearance by a tumor necrosis factor-alpha-dependent mechanism.

To study the rate and regulation of alveolar fluid clearance in acute pneumonia, we created a model of Pseudomonas aeruginosa pneumonia in rats. To measure alveolar liquid and protein clearance, we instilled into the airspaces a 5% bovine albumin solution with 1.5 microCi of 125I-human albumin, 24 h after intratracheal instillation of bacteria. The concentration of unlabeled and labeled protein in the distal airspaces over 1 h was used as an index of net alveolar fluid clearance. Since there was histologic evidence of alveolar epithelial injury, several methods were used to measure alveolar fluid clearance, including the use of experiments in rats with blood flow and the use of experiments in rats without blood flow, so that movement across the epithelial barrier would be minimized in the latter group. The results with each method were identical. We found that P. aeruginosa pneumonia increased alveolar liquid clearance over 1 h by 48% in studies with blood flow, and by 43% in rats without blood flow, compared with respective controls (P < 0.05). In both studies, this increase was inhibited with amiloride. However, propranolol had no inhibitory effect, thus ruling out a catecholamine-dependent mechanism to explain the increase in alveolar fluid clearance. An antitumor necrosis factor-alpha neutralizing antibody, instilled into the lung 5 min before bacteria, prevented the increase in alveolar liquid clearance in rats with pneumonia (P < 0.05). Also, TNFalpha (5 microg) instilled in normal rats increased alveolar liquid clearance by 43% over 1 h compared with control rats (P < 0.05). In normal rats instilled with TNFalpha, propranolol had no inhibitory effect. In conclusion, gram-negative pneumonia markedly upregulates net alveolar epithelial fluid clearance, in part by a TNFalpha-dependent mechanism. This finding provides a novel mechanism for the upregulation of alveolar epithelial sodium and fluid transport from the distal airspaces of the lung.

Adrenergic beta-Antagonists↗
PubMed1997

Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study.

OBJECTIVE: To evaluate the incidence, clinical features, and prognosis of pulmonary complications associated with toxic epidermal necrolysis DESIGN: Prospective study. SETTING: Dermatology intensive care unit in Mondor Hospital, France. PATIENTS: 41 consecutive patients. INTERVENTIONS: On admission, then daily, respiratory evaluation was based on clinical examination, chest X-ray, and arterial blood gas analysis. When clinical symptoms, X-ray abnormalities, or hypoxemia [partial pressure of oxygen (PO2) < 80 mm Hg] were present, fiberoptic bronchoscopy was performed. RESULTS: 10 patients presented early manifestations: dyspnea (n = 10), bronchial hypersecretion (n = 7), marked hypoxemia (n = 10) (PO2 = 59 +/- 8 mm Hg). Chest X-ray was normal (n = 8) or showed interstitial infiltrates (n = 2). In these 10 patients, fiberoptic bronchoscopy demonstrated sloughing of bronchial epithelium in proximal airways. Delayed pulmonary complications occurred in 6 of these 10 patients from day 7 to day 15: pulmonary edema (n = 2), atelectasis (n = 1), bacterial pneumonitis (n = 4). Mechanical ventilation was required in 9 patients. A fatal outcome occurred in 7 patients. Seven patients did not develop early pulmonary manifestations (PO2 on admission 87 +/- 6 mm Hg) but only delayed pulmonary symptoms related to atelectasis (n = 1), pulmonary edema (n = 4), and bacterial pneumonitis (n = 3); bronchial epithelial detachment was not observed. None of them required mechanical ventilation and all recovered with appropriate therapy. CONCLUSIONS: "Specific" involvement of bronchial epithelium was noted in 27% of cases and must be suspected when dyspnea, bronchial hypersecretion, normal chest X-ray, and marked hypoxemia are present during the early stages of toxic epidermal necrosis. Bronchial injury seems to indicate a poor prognosis, as mechanical ventilation was required for most of these patients and was associated with a high mortality.

Adolescent↗
PubMed1997

Carbon dioxide respiratory response during positive inspiratory pressure in COPD patients.

The aim of this study was to compare the effect of inspiratory pressure support (IPS) on the respiratory CO2 response in 13 stable COPD patients and in 13 normal subjects. Without IPS, the slopes of the ventilatory response to CO2 were lower in the patients than in the normal subjects (mean +/- SEM, 0.82 +/- 0.19 vs. 1.69 +/- 0.31 l.min-1.mmHg-1). When IPS was applied, both groups showed, at any level of end-tidal CO2 pressure, an increase in ventilation due to an increase in tidal volume (VT) associated with a decrease in occlusion pressure (P0.1). In addition, respiratory parameters (VE, VT, P0.1, inspiratory flow) were insensitive to CO2 as long as PETCO2 remained below a threshold which was slightly above the eupneic value. However, above this CO2-threshold, no differences in slopes were observed between the IPS and control conditions in either group, except for a decrease in the P0.1 slope during IPS in the COPD patients. In conclusion, IPS induced similar respiratory changes during CO2 response in stable COPD patients and in normal subjects. Above the eupneic value, IPS did not change the slope of the ventilatory response to CO2.

Adult↗
PubMed1997

Gelatinases in epithelial lining fluid of patients with adult respiratory distress syndrome.

Gelatinases A and B are matrix metalloproteinases secreted as inactive pro forms and are capable of degrading basement membrane components after activation in the extracellular environment. To determine whether the presence of gelatinases A (noninflammatory cells) and B (inflammatory cells) in epithelial lining fluid (ELF) is associated with the adult respiratory distress syndrome (ARDS), we studied 28 patients divided into four groups based on the presence of ARDS and/or multiple organ failure (MOF). Gelatinase activities were quantified in ELF using zymography. ARDS patients had larger ELF volumes than non-ARDS patients: 9.2 +/- 8.5 ml/100 ml recovered lavage fluid (n = 18) vs. 1.9 +/- 1.7 ml/100 ml (n = 11), respectively (P < 0.001). The presence of activated gelatinase A in ELF was a sensitive (16 out of 18 ARDS patients, 89%) and specific (0 out of 11 non-ARDS patients with or without MOF) marker for ARDS. Activated gelatinase (A + B) activities per microliter ELF were correlated with albumin concentrations in ELF (P < 0.01), and activated gelatinase activities in ELF were correlated with the volume of ELF (P < 0.0005). This could suggest an involvement of these gelatinases in alveolar-capillary permeability increase.

Adult↗
PubMed1997

Alveolar neutrophils in endotoxin-induced and bacteria-induced acute lung injury in rats.

Polymorphonuclear neutrophils (PMNs) are thought to play a major role in the pathogenesis of adult respiratory distress syndrome. Because the alveolar epithelium is a decisive factor in alveolo-capillary wall permeability, a toxic effect of emigrated PMNs in alveolar spaces is conceivable. We evaluated alveolar PMN function in two rat models of acute lung injury induced by alveolar instillation of endotoxin [lipopolysaccharide (LPS)] or live Pseudomonas aeruginosa (PYO). Alveolar PMNs were isolated from bronchoalveolar lavage fluid 4 and 24 h after the challenge. Hypoxemia was assessed based on the ratio arterial partial pressure of O2 (PaO2)/fraction of inspired O2 (FIO2) during mechanical ventilation. The severity of lung injury in the two models was clearly different, since PaO2/FIO2 were approximately 400 mmHg in PYO- and LPS-induced injuries, respectively. Both contrast, alveolar neutrophil influx, unstimulated oxygen metabolite production, and proteinase (elastase, gelatinase B) secretions of ex vivo alveolar PMNs were not larger in the PYO model. Thus the difference in severity was not associated with variations in alveolar neutrophil recruitment or activation. Moreover, gelatinase and leukocyte elastase activities were absent in bronchoalveolar fluid, indicating effective antiproteinase defense in alveolar spaces. We conclude that alveolar neutrophils are not sufficient to create severe respiratory failure.

Animals↗
PubMed1997

Alveolar epithelial cells in vitro produce gelatinases and tissue inhibitor of matrix metalloproteinase-2.

Type II pneumocytes are key cells of the alveolar epithelium. They lie on the alveolar basement membrane, which influences their phenotype and functions. We hypothesized that type II pneumocytes degrade basement membrane components by producing gelatinases, members of the matrix metalloproteinase family. To investigate this hypothesis, we used primary cultures of rat type II pneumocytes and cultures of the human A549 cell line. We found by zymography that 70-kDa gelatinase was present in media conditioned by these cells. This 70-kDa gelatinase was identified as gelatinase A by a Western blot, and the presence of its mRNA was demonstrated by reverse transcription-polymerase chain reaction. A 95-kDa gelatinase could be induced under certain conditions. Production of gelatinases may take place during the turnover of basement membranes, in physiological and in pathophysiological processes. This was suggested by the increase in production of both gelatinases that we observed after in vitro exposure to LPS or interleukin-1. The presence of tissue inhibitors of matrix metalloproteinase-1 and -2 was also demonstrated, suggesting that degradation of extracellular matrix by type II pneumocytes is tightly regulated.

Animals↗
PubMed1997

Modulatory effects of PKC activity on increased 92-kDa gelatinase secretion by neonatal alveolar macrophages.

We previously demonstrated that alveolar macrophages (AMs) from neonatal rats can secrete more 92-kDa gelatinase than AMs from adult rats. In this study, we investigated the role of the protein kinase C (PKC) pathway in the transductional regulation of 92-kDa gelatinase secretion by rat AMs, and we also evaluated maturational changes in this role with increasing postnatal age. After AM stimulation by phorbol 12-myristate 13-acetate (PMA), we observed a dose-dependent increase in gelatinase secretion that was significantly more marked in AMs from 6-day-old rats than in AMs from adult rats and that was inhibited by the PKC inhibitor calphostin C. Adenosine 3',5'-cyclic monophosphate mimetics or concanavalin A failed to induce an increase in gelatinase secretion by AMs. Time-dependent variations in PKC activity after PMA stimulation differed significantly between 6-day-old rats and adult rats; PKC activity decreased in adult AMs (50%) but remained stable in 6-day-old AMs. We therefore investigated age-related differences in the intracellular proteolytic degradation of PKC, which is thought to be mediated by calpains. Leupeptin, used as a calpain inhibitor, inhibited the decrease in PKC activity after exposure of adult AMs to PMA and induced a greater than threefold increase in PMA-induced gelatinase secretion. Calpain activity was significantly lower in AM extracts from 6-day-old than from adult rats. The physiological implication of these developmental changes in 92-kDa gelatinase regulation was demonstrated by investigation of AMs from 1-day-old rats that showed a high level of spontaneous PKC-dependent gelatinase secretion coexisting with very low calpain activity. We conclude that sustained PKC activity is a key factor in the increased gelatinase secretion by AMs seen during the postnatal period and is due, at least in part, to reduced PKC degradation.

Aging↗