PubMed Health⌕ Search

Biomedical subjects

Jean-François Pittet

Publications and source records attributed to Jean-François Pittet.

13 recordsLinked to original sources
PubMed2006

Integrin alphavbeta5 regulates lung vascular permeability and pulmonary endothelial barrier function.

Increased lung vascular permeability is an important contributor to respiratory failure in acute lung injury (ALI). We found that a function-blocking antibody against the integrin alphavbeta5 prevented development of lung vascular permeability in two different models of ALI: ischemia-reperfusion in rats (mediated by vascular endothelial growth factor [VEGF]) and ventilation-induced lung injury (VILI) in mice (mediated, at least in part, by transforming growth factor-beta [TGF-beta]). Knockout mice homozygous for a null mutation of the integrin beta5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of alphavbeta5 prevented increases in monolayer permeability induced by VEGF, TGF-beta, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking alphavbeta5, suggesting that alphavbeta5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin alphavbeta5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.

Amides↗
PubMed2006

Integrating acute lung injury and regulation of alveolar fluid clearance.

The acute respiratory distress syndrome (ARDS) is characterized by non-cardiogenic pulmonary edema and flooding of the alveolar air spaces with proteinaceous fluid. ARDS develops in response to inflammatory stresses including sepsis, trauma, and severe pneumonia, and despite aggressive critical care management, it still has a mortality of 30-50%. At the time of its original description in 1967, relatively little was known about the specific mechanisms by which the alveolar epithelium regulated lung fluid balance. Over the last 20 years, substantial advances in our understanding of the alveolar epithelium have provided major new insights into how molecular and cellular mechanisms regulate the active transport of solutes and fluid across the alveolar epithelium under both normal and pathological conditions. Beginning with the elucidation of active sodium transport as a major driving force for the transport of water from the air space to the interstitium, elegant work by multiple investigators has revealed a complex and integrated network of membrane channels and pumps that coordinately regulates sodium, chloride, and water flux in both a cell- and condition-specific manner. At the Experimental Biology Meeting in San Francisco on April 4, 2006, a symposium was held to discuss some of the most recent advances. Although there is still much to learn about the mechanisms that impair normal alveolar fluid clearance under pathological conditions, the compelling experimental findings presented in this symposium raise the prospect that we are now poised to test and develop therapeutic strategies to improve outcome in patients with acute lung injury.

Adrenergic Agents↗
PubMed2006

Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury.

Previous studies have shown that heat shock protein 72 (Hsp72) is found in the extracellular space (eHsp72) and that eHsp72 has potent immunomodulatory effects. However, whether eHsp72 is present in the distal air spaces and whether eHsp72 could modulate removal of alveolar edema is unknown. The first objective was to determine whether Hsp72 is released within air spaces and whether Hsp72 levels in pulmonary edema fluid would correlate with the capacity of the alveolar epithelium to remove alveolar edema fluid in patients with ALI/ARDS. Patients with hydrostatic edema served as controls. The second objective was to determine whether activation of the stress protein response (SPR) caused the release of Hsp72 into the extracellular space in vivo and in vitro and to determine whether SPR activation and/or eHsp72 itself would prevent the IL-1beta-mediated inhibition of the vectorial fluid transport across alveolar type II cells. We found that eHsp72 was present in plasma and pulmonary edema fluid of ALI patients and that eHsp72 was significantly higher in pulmonary edema fluid from patients with preserved alveolar epithelial fluid clearance. Furthermore, SPR activation in vivo in mice and in vitro in lung endothelial, epithelial, and macrophage cells caused intracellular expression and extracellular release of Hsp72. Finally, SPR activation, but not eHsp72 itself, prevented the decrease in alveolar epithelial ion transport induced by exposure to IL-1beta. Thus SPR may protect the alveolar epithelium against oxidative stress associated with experimental ALI, and eHsp72 may serve as a marker of SPR activation in the distal air spaces of patients with ALI.

Adult↗
PubMed2005

Serum levels of Hsp60 correlate with the development of acute lung injury after trauma.

BACKGROUND: Previous studies have shown that heat shock protein 60 (Hsp60) is a danger signal for the immune system and appears to be a key endogenous inflammatory mediator that activates the toll-like receptors and causes the release of proinflammatory cytokines and nitric oxide by immune competent cells, but no data are available for trauma patients. The purpose of this study was to determine whether Hsp60 could be detected in the serum of patients early after severe trauma and whether its serum level might correlate with the development of acute lung injury (ALI) in trauma patients. METHODS: Clinical data were collected prospectively during a 12-month period for trauma patients who were ventilated mechanically for more than 24 h and who met the following inclusion criteria: Injury Severity Score > or =16, age >18 years. Physiological data for quantitative assessment of organ dysfunction were collected for each patient. Hsp60 levels were measured in the serum of trauma patients. RESULTS: Sixty-four patients with severe trauma were enrolled in the study. Eighteen patients developed ALI (28%). Trauma patients who later developed ALI had significantly higher serum values of Hsp60 than those who did not (4.21 +/- 2.24 ng/mL versus 0.73 +/- 0.26 ng/mL, P < 0.05, mean +/- SE). Furthermore, immature but not mature recombinant Hsp60 induced in vitro the release of nitric oxide (NO) from RAW 264.7 murine macrophages. CONCLUSION: Serum levels of Hsp60 detected within 30 min after trauma correlate with the development of ALI. Immature but mature Hsp60 causes in vitro the release of NO by macrophages, suggesting that the extracellular release of the immature Hsp60 associated with traumatic cell necrosis could be involved in the release of NO by immune competent cells, leading to an activation of the inflammatory response within the lung or other organs.

Adult↗
PubMed2005

Interleukin-1beta decreases expression of the epithelial sodium channel alpha-subunit in alveolar epithelial cells via a p38 MAPK-dependent signaling pathway.

Acute lung injury (ALI) is a devastating syndrome characterized by diffuse alveolar damage, elevated airspace levels of pro-inflammatory cytokines, and flooding of the alveolar spaces with protein-rich edema fluid. Interleukin-1beta (IL-1beta) is one of the most biologically active cytokines in the distal airspaces of patients with ALI. IL-1beta has been shown to increase lung epithelial and endothelial permeability. In this study, we hypothesized that IL-1beta would decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we measured the effects of IL-1beta on transepithelial current, resistance, and sodium transport in primary cultures of alveolar epithelial type II (ATII) cells. IL-1beta significantly reduced the amiloride-sensitive fraction of the transepithelial current and sodium transport across rat ATII cell monolayers. Moreover, IL-1beta decreased basal and dexamethasone-induced epithelial sodium channel alpha-subunit (alpha ENaC) mRNA levels and total and cell-surface protein expression. The inhibitory effect of IL-1beta on alpha ENaC expression was mediated by the activation of p38 MAPK in both rat and human ATII cells and was independent of the activation of alpha v beta6 integrin and transforming growth factor-beta. These results indicate that IL-1beta may contribute to alveolar edema in ALI by reducing distal lung epithelial sodium absorption. This reduction in ion and water transport across the lung epithelium is in large part due to a decrease in alpha ENaC expression through p38 MAPK-dependent inhibition of alpha ENaC promoter activity and to an alteration in ENaC trafficking to the apical membrane of ATII cells.

Animals↗
PubMed2004

Apoptosis inhibition in P. aeruginosa-induced lung injury influences lung fluid balance.

OBJECTIVE: Pseudomonas aeruginosa-induced lung injury is characterized not only by the alteration in lung fluid movement but also by apoptosis of lung epithelial and endothelial cells. We studied whether inhibition of apoptosis using a broad spectrum caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (Z-VAD.fmk), would affect lung fluid balance in rat P. aeruginosa pneumonia. METHODS: Z-VAD.fmk (3 mg/kg) was administered intravenously simultaneously with P. aeruginosa intratracheal instillation (0.5 ml/kg, 2 x 10(9) CFU/ml). Apoptosis was evaluated with the TUNEL technique, cytoplasmic oligonucleosome assay, and caspase 3 activation. To evaluate lung permeability, extravascular plasma equivalent (EPE) and lung wet to dry weight ratio (W/D) were measured 4 h after intratracheal instillation of P. aeruginosa. RESULTS: We found an increase of lung apoptosis 4 h after P. aeruginosa instillation: cytoplasmic oligonucleosome assay increased from 3.17+/-0.78 to 26.82+/-4.67 ODx1000/mg of proteins/ml, Z-VAD.fmk administration decreased this parameter to 10.3+/-2.98 ODx1000/mg of proteins/ml. Caspase 3 levels followed the same pattern. Apoptosis involved both epithelial cells and endothelial cells. Endothelial permeability was increased after Pseudomonas instillation: W/D increased from 3.75+/-0.28 in the Co group to 4.42+/-0.23 in the Pn group; EPE was also higher in the Pn group compared with the Co group (0.125+/-0.04 and 0.002+/-0.01 ml, respectively). Both of these parameters were improved after Z-VAD.fmk administration; W/D decreased to 3.36+/-0.25 and EPE to 0.02+/-0.02 ml. CONCLUSION: Apoptosis occurs in the early phase of P. aeruginosa pneumonia. Administration of Z-VAD.fmk significantly decreases DNA fragmentation and caspase 3 levels. This is associated with an improvement of endothelial permeability and lung fluid balance.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Prognostic value of the pulmonary dead-space fraction during the first 6 days of acute respiratory distress syndrome.

BACKGROUND: The ratio of pulmonary dead space to tidal volume (VD/VT) in acute respiratory distress syndrome (ARDS) is reported to be between 0.35 and 0.55. However, VD/VT has seldom been measured with consideration to the evolving pathophysiology of ARDS. METHODS: We made serial VD/VT measurements with 59 patients who required mechanical ventilation for > or = 6 days. We measured VD/VT within 24 h of the point at which the patient met the American-European Consensus Conference criteria for ARDS, and we repeated the VD/VT measurement on ARDS days 2, 3, and 6 with a bedside metabolic monitor during volume-regulated ventilation. We analyzed the changes in VD/VT over the 6-day period to determine whether VD/VT has a significant association with mortality. RESULTS: VD/VT was significantly higher in nonsurvivors on day 1 (0.61 +/- 0.09 vs 0.54 +/- 0.08, p < 0.05), day 2 (0.63 +/- 0.09 vs 0.53 +/- 0.09, p < 0.001), day 3 (0.64 +/- 0.09 vs 0.53 +/- 0.09, p < 0.001), and day 6 (0.66 +/- 0.09 vs 0.51 +/- 0.08, p < 0.001). CONCLUSION: In ARDS a sustained VD/VT elevation is characteristic of nonsurvivors, so dead-space measurements made beyond the first 24 hours may have prognostic value.

Age Factors↗
PubMed2003

Transforming growth factor-beta1 decreases expression of the epithelial sodium channel alphaENaC and alveolar epithelial vectorial sodium and fluid transport via an ERK1/2-dependent mechanism.

Acute lung injury (ALI) is characterized by the flooding of the alveolar airspaces with protein-rich edema fluid and diffuse alveolar damage. We have previously reported that transforming growth factor-beta1 (TGF-beta1) is a critical mediator of ALI after intratracheal administration of bleomycin or Escherichia coli endotoxin, at least in part due to effects on lung endothelial and alveolar epithelial permeability. In the present study, we hypothesized that TGF-beta1 would also decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we studied the effect of active TGF-beta1 on 22Na+ uptake across monolayers of primary rat and human alveolar type II (ATII) cells. TGF-beta1 significantly reduced the amiloride-sensitive fraction of 22Na+ uptake and fluid transport across monolayers of both rat and human ATII cells. TGF-beta1 also significantly decreased alphaENaC mRNA and protein expression and inhibited expression of a luciferase reporter downstream of the alphaENaC promoter in lung epithelial cells. The inhibitory effect of TGF-beta1 on sodium uptake and alphaENaC expression in ATII cells was mediated by activation of the MAPK, ERK1/2. Consistent with the in vitro results, TGF-beta1 inhibited the amiloride-sensitive fraction of the distal airway epithelial fluid transport in an in vivo rat model at a dose that was not associated with any change in epithelial protein permeability. These data indicate that increased TGF-beta1 activity in the distal airspaces during ALI promotes alveolar edema by reducing distal airway epithelial sodium and fluid clearance. This reduction in sodium and fluid transport is attributable in large part to a reduction in apical membrane alphaENaC expression mediated through an ERK1/2-dependent inhibition of the alphaENaC promoter activity.

Amiloride↗
PubMed2003

Postdural puncture headache in a parturient with sickle cell disease: use of an epidural colloid patch.

PURPOSE: To report the injection of a colloid in the epidural space as an alternative to an epidural blood patch in a woman with sickle cell disease. CLINICAL FEATURES: A Cesarean delivery was performed under spinal anesthesia in a 32-yr-old woman with severe sickle cell disease and a past medical history of vaso-occlusive crisis. In the postoperative period, the patient complained of postdural puncture headache resistant to symptomatic treatment. Because there were no data concerning the safety of a blood patch in this condition, a colloid (a modified fluid gelatin heated to 37 degrees C) was injected in the epidural space instead of blood. Headaches decreased immediately after the epidural injection of the colloid and disappeared totally within 12 hr. CONCLUSION: Data concerning the safety of epidural blood patches in patients with sickle cell disease are lacking. Injection of colloids in the epidural space could be an alternative.

Adult↗
PubMed2003

Description and evaluation of a delivery system for aerosolized prostacyclin.

INTRODUCTION: Inhaled vasodilators such as nitric oxide and aerosolized prostacyclin (PGI(2)) are used to treat severe hypoxemia in acute respiratory distress syndrome. Preferential distribution of nitric oxide and PGI(2) to ventilated areas of the lung causes selective pulmonary vasodilation, improved ventilation/perfusion matching, and decreased hypoxemia. Because of the technical limitations of previously described methods, we developed a PGI(2) delivery technique that allows the aerosolized drug dose to be easily calculated, set, and adjusted. METHODS: A 50 mL solution of PGI(2) (3.0x10(4) ng/mL) and a 500 mL normal saline solution were infused by a dual-channel volumetric infusion pump into a MiniHEART jet nebulizer that has a manufacturer-specified output of 8 mL/h at a set flow of 2 L/min. By adjusting the pump infusion rate to achieve a total output of 8 mL/h, the PGI(2) concentration was altered to deliver a calculated aerosolized dose of 10-50 ng/kg/min. The effectiveness of the delivery system was retrospectively evaluated by way of the responses of 11 severely hypoxemic acute respiratory distress syndrome patients who received PGI(2) via the system we describe. The MiniHEART nebulizer output, particle size, and dose delivery were evaluated in a laboratory bench study, using a set flow of 2 L/min. RESULTS: Aerosolized PGI(2) therapy (mean dose 28 +/- 17 ng/kg/min, range 10-50 ng/kg/min) significantly increased the ratio of P(aO)(2) to fraction of inspired oxygen (P(aO)(2)/F(IO)(2)) (60 +/- 11 mm Hg vs 80 +/- 17 mm Hg, p = 0.003) and arterial oxygen saturation measured via pulse oximetry (86 +/- 8% vs 94 +/- 3%, p = 0.005) (differences evaluated with the Wilcoxon signed rank test). There was no difference in positive end-expiratory pressure, mean airway pressure, or F(IO)(2), before and after aerosolized PGI(2) (p > 0.05). Nebulizer output was 6.8 +/- 0.9 mL/h, range 6.0-7.8 mL/h. The inhaled aerosol particles had a mass median diameter of 3.1 micro m. Emitted dose was 67 +/- 13% (range 57-81%) of the calculated dose. CONCLUSION: Our system is effective in delivering aerosolized PGI(2) to the alveolar-capillary interface, as indicated by significant oxygenation improvements soon after therapy commenced. The performance of the MiniHEART nebulizer varies from the manufacturer's specifications, which may alter the delivered dose.

Administration, Inhalation↗
PubMed2002

Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome.

BACKGROUND: No single pulmonary-specific variable, including the severity of hypoxemia, has been found to predict the risk of death independently when measured early in the course of the acute respiratory distress syndrome. Because an increase in the pulmonary dead-space fraction has been described in observational studies of the syndrome, we systematically measured the dead-space fraction early in the course of the illness and evaluated its potential association with the risk of death. METHODS: The dead-space fraction was prospectively measured in 179 intubated patients, a mean (+/-SD) of 10.9+/-7.4 hours after the acute respiratory distress syndrome had developed. Additional clinical and physiological variables were analyzed with the use of multiple logistic regression. The study outcome was mortality before hospital discharge. RESULTS: The mean dead-space fraction was markedly elevated (0.58+/-0.09) early in the course of the acute respiratory distress syndrome and was higher among patients who died than among those who survived (0.63+/-0.10 vs. 0.54+/-0.09, P<0.001). The dead-space fraction was an independent risk factor for death: for every 0.05 increase, the odds of death increased by 45 percent (odds ratio, 1.45; 95 percent confidence interval, 1.15 to 1.83; P=0.002). The only other independent predictors of an increased risk of death were the Simplified Acute Physiology Score II, an indicator of the severity of illness (odds ratio, 1.06; 95 percent confidence interval, 1.03 to 1.08; P<0.001) and quasistatic respiratory compliance (odds ratio, 1.06; 95 percent confidence interval, 1.01 to 1.10; P=0.01). CONCLUSIONS: Increased dead-space fraction is a feature of the early phase of the acute respiratory distress syndrome. Elevated values are associated with an increased risk of death.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Serum levels of Hsp 72 measured early after trauma correlate with survival.

BACKGROUND: Experimental studies have shown that hemorrhagic shock is associated with the expression of inducible heat proteins, especially heat shock protein (Hsp) 72, in liver, brain, heart, and kidney. Moreover, induction of Hsp 72 by various stressors before the onset of shock has been associated with the attenuation of organ injury caused by hemorrhage. However, it is not known whether Hsp 72 is expressed after severe trauma in humans. The purpose of this study was therefore to determine whether Hsp 72 could be detected in the serum of patients early after severe trauma and whether serum levels of Hsp 72 might correlate with survival of trauma patients or the severity of the postinjury inflammatory response. METHODS: Clinical data were collected prospectively over a 3-year period for trauma patients mechanically ventilated for more than 2 days who met the following inclusion criteria: Injury Severity Score > or = 16, and age > 18 years. Physiologic data for quantitative assessment of organ dysfunction were collected for each patient. Hsp 72 and nitrate and nitrite levels were measured in the serum of trauma patients collected at or 12 to 48 hours after the admission to the emergency department. RESULTS: Sixty-seven patients with severe trauma were enrolled in the study. Hsp 72 was detected in the serum of all trauma patients. All patients with high initial serum levels of Hsp 72 (serum levels > 15 ng/mL) survived, whereas 29% of the patients with low Hsp 72 serum levels died from their traumatic injuries (p = 0.01). The overall mortality was 21%, occurring within 5 to 7 days. Patients who died were older (mean age, 54 +/- 15 years) than those who survived (mean age, 36 +/- 15 years) (p < 0.0.05). The cause of death was attributable to head injury in 79%, although the severity of head injury (Abbreviated Injury Scale score) was not statistically different between survivors with high serum values of Hsp 72 and patients who died. There was no correlation between the initial serum Hsp 72 values and the severity of organ dysfunction or clinical indicators of the inflammatory response. CONCLUSION: Hsp 72 can be detected in the serum of severely traumatized patients within 30 minutes after injury. Elevated initial serum levels of Hsp 72 (serum levels > 15 ng/mL) are associated with survival after severe trauma, but are not related to the incidence or severity of the postinjury inflammatory response or organ dysfunction.

Analysis of Variance↗