Biomedical subjects

Michael A Matthay

Publications and source records attributed to Michael A Matthay.

At least 91 records · Page 5Linked to original sources

PubMed2004

Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury.

OBJECTIVE: To determine whether clinically relevant airspace concentrations of beta2-adrenergic agonists stimulated maximal alveolar fluid clearance rates and to determine whether beta2 agonist therapy decreased pulmonary edema in experimental acute lung injury. DESIGN: Prospective randomized laboratory investigation. SETTING: University-affiliated laboratory. SUBJECTS: Sprague Dawley rats. INTERVENTIONS: Dibutyryl cyclic adenosine monophosphate (cAMP), salmeterol, albuterol, and isoproterenol in normal rat lung. Salmeterol in a rat model of acid-induced lung injury. MEASUREMENTS AND MAIN RESULTS: Basal alveolar fluid clearance was 7.6 +/- 2.2 %/hr. Maximal cAMP-dependent alveolar fluid clearance rate was 32.9 +/- 10.9 %/hr (p <.05). Racemic albuterol 10(-5) M, salmeterol 10(-6) M, and isoproterenol 10(-6) M each stimulated alveolar fluid clearance to a level comparable to maximal cAMP-dependent alveolar fluid clearance. Compared with basal rates, alveolar fluid clearance was increased by both racemic albuterol 10(-6) M (14.5 +/- 3.0%, p <.05) and R-enantiomer 10(-6) M (15.0 +/- 4.6%, p <.05), but there was no difference between the two groups. Intra-alveolar salmeterol 10 (-6) M attenuated the degree of pulmonary edema following acid-induced lung injury. Extravascular lung water increased to only 180 +/- 30 microL with salmeterol treatment, compared with 296 +/- 65 microL in saline-treated rats 4 hrs after acid injury (p <.05). This decrease in lung water was accompanied by a 2.4-fold increase in the rate of alveolar fluid clearance at 4 hrs in the salmeterol-treated group. Lung endothelial permeability, expressed as extravascular plasma equivalents, was reduced to 64 +/- 9 microL with salmeterol compared with 119 +/- 51 microL in saline-treated rats 4 hrs after acid injury (p <.05). CONCLUSIONS: Clinically relevant airspace concentrations of beta2-adrenergic agonists a) stimulate maximal cAMP-dependent airspace fluid clearance in normal lungs and b) reduce pulmonary edema in acid aspiration-induced lung injury by increasing alveolar fluid clearance and decreasing endothelial permeability. Clinical studies are required to determine whether beta2-adrenergic agonists improve outcome in patients with acute lung injury.

Adenosine Monophosphate↗

PubMed2004

Mechanisms of alveolar protein clearance in the intact lung.

Transport of protein across the alveolar epithelial barrier is a critical process in recovery from pulmonary edema and is also important in maintaining the alveolar milieu in the normal healthy lung. Various mechanisms have been proposed for clearing alveolar protein, including transport by the mucociliary escalator, intra-alveolar degradation, or phagocytosis by macrophages. However, the most likely processes are endocytosis across the alveolar epithelium, known as transcytosis, or paracellular diffusion through the epithelial barrier. This article focuses on protein transport studies that evaluate these two potential mechanisms in whole lung or animal preparations. When protein concentrations in the air spaces are low, e.g., albumin concentrations <0.5 g/100 ml, protein transport demonstrates saturation kinetics, temperature dependence indicating high energy requirements, and sensitivity to pharmacological agents that affect endocytosis. At higher concentrations, the protein clearance rate is proportional to protein concentration without signs of saturation, inversely related to protein size, and insensitive to endocytosis inhibition. Temperature dependence suggests a passive process. Based on these findings, alveolar albumin clearance occurs by receptor-mediated transcytosis at low protein concentrations but proceeds by passive paracellular mechanisms at higher concentrations. Because protein concentrations in pulmonary edema fluid are high, albumin concentrations of 5 g/100 ml or more, clearance of alveolar protein occurs by paracellular pathways in the setting of pulmonary edema. Transcytosis may be important in regulating the alveolar milieu under nonpathological circumstances. Alveolar degradation may become important in long-term protein clearance, clearance of insoluble proteins, or under pathological conditions such as immune reactions or acute lung injury. acute respiratory distress syndrome; endocytosis; diffusion; protein transport pulmonary edema

Animals↗

PubMed2004

Integrated control of lung fluid balance.

This review summarizes the highlights of the EB2004 symposium that dealt with the integrated aspects of the lung fluid balance. It is apparent that maintenance of lung fluid balance requires the proper functioning of vascular endothelial and alveolar epithelial barriers. Under physiological conditions, the transcytotic pathway requiring repeated fission-fusion events of the caveolar membrane with other caveolae solely transports albumin. Caveolin-1, which forms caveolae, and albumin-binding proteins play a central role in signaling the transcytosis of albumin. Signals responsible for increasing endothelial permeability in lung microvessels in response to inflammatory mediators were also described. These studies in gene knockout mouse models revealed the importance of Ca(2+) signaling via store-operated transient receptor channel 4 and the activation of endothelial myosin light chain kinase isoform in mediating the increase in microvessel permeability. Increases in the cytosolic Ca(2+) in situ in microvessel endothelia can occur by mitochondria-dependent as well as mitochondria-independent pathways (such as the endoplasmic reticulum). Both these pathways, by triggering endothelial cell activation, may result in lung microvascular injury. The resolution of alveolar edema, requiring clearance of fluid from the air space, is another area of intense investigation in animal models. Although beta-adrenergic agonists can activate alveolar fluid clearance, signaling pathways regulating these events in intact alveoli remain to be established. Development of mouse models in which the function of regulatory proteins (identified in cell culture studies) can be systematically analyzed will provide a better and more integrated picture of lung fluid balance. In vivo veritas!

Animals↗

PubMed2004

Proteomics: current techniques and potential applications to lung disease.

Proteomics aims to study the whole protein content of a biological sample in one set of experiments. Such an approach has the potential value to acquire an understanding of the complex responses of an organism to a stimulus. The large vascular and air space surface area of the lung expose it to a multitude of stimuli that can trigger a variety of responses by many different cell types. This complexity makes the lung a promising, but also challenging, target for proteomics. Important steps made in the last decade have increased the potential value of the results of proteomics studies for the clinical scientist. Advances in protein separation and staining techniques have improved protein identification to include the least abundant proteins. The evolution in mass spectrometry has led to the identification of a large part of the proteins of interest rather than just describing changes in patterns of protein spots. Protein profiling techniques allow the rapid comparison of complex samples and the direct investigation of tissue specimens. In addition, proteomics has been complemented by the analysis of posttranslational modifications and techniques for the quantitative comparison of different proteomes. These methodologies have made the application of proteomics on the study of specific diseases or biological processes under clinically relevant conditions possible. The quantity of data that is acquired with these new techniques places new challenges on data processing and analysis. This article provides a brief review of the most promising proteomics methods and some of their applications to pulmonary research.

Animals↗

PubMed2004

Coagulation-dependent mechanisms and asthma.

In several clinical disorders, there are interactions between inflammation-dependent tissue injury and thrombin formation, fibrin deposition, and impaired fibrinolysis. New evidence generated from a mouse model of allergic airway hyperreactivity suggests that disordered coagulation and fibrinolysis may contribute to the pathogenesis of asthma. The inflammatory mechanisms that lead to airway smooth muscle contraction and airway hyperresponsiveness may be associated with accumulation of extravascular fibrin, plasma exudates, and inflammatory cells that can lead to airway closure.

Asthma↗

PubMed2004

Transfusion-related acute lung injury: a review.

Transfusion-related acute lung injury (TRALI) is an underreported complication of transfusion therapy, and it is the third most common cause of transfusion-associated death. TRALI is defined as noncardiogenic pulmonary edema temporally related to transfusion therapy. The diagnosis of TRALI relies on excluding other diagnoses such as sepsis, volume overload, and cardiogenic pulmonary edema. Supportive diagnostic evidence includes identifying neutrophil or human leukocyte antigen (HLA) antibodies in the donor or recipient plasma. All plasma-containing blood products have been implicated in TRALI, with the majority of cases linked to whole blood, packed RBCs, platelets, and fresh-frozen plasma. The pathogenesis of TRALI may be explained by a "two-hit" hypothesis, with the first "hit" being a predisposing inflammatory condition commonly present in the operating room or ICU. The second hit may involve the passive transfer of neutrophil or HLA antibodies from the donor or the transfusion of biologically active lipids from older, cellular blood products. Treatment is supportive, with a prognosis substantially better than most causes of clinical acute lung injury.

Adult↗

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

Effect of continuous hemofiltration on hemodynamics, lung inflammation and pulmonary edema in a canine model of acute lung injury.

OBJECTIVE: This study examined whether continuous hemofiltration favorably affects cardiopulmonary variables, lung inflammation, and lung fluid balance in a canine model of oleic acid induced acute lung injury. METHODS: Eleven pentobarbital-anesthetized dogs were randomly divided into a control (mechanical ventilation, MV) group (n=6) and a MV plus hemofiltration (HF) group (n=5). All animals received an intravenous injection of oleic acid (0.09 ml/kg) to induce acute lung injury. Continuous arterial-venous hemofiltration (blood flow 100 ml/min, ultrafiltration rate at 50-65 ml kg(-1) h(-1)) was started after establishment of oleic acid induced acute lung injury and continued for 4 h. Hemodynamics, lung mechanics, gas exchange, lung fluid balance, lung histology, and the level of plasma cytokines were assessed. RESULTS: After 240 min of HF treatment there was a significant increase in cardiac output, reduction in pulmonary arterial pressure, and improvement in both oxygenation and lung mechanics. Also, in the HF group the lung wet-to-dry weight ratio was significantly reduced. Histologically, HF reduced edema and inflammatory cell infiltration in the lung. There was also a significantly greater decrease in plasma IL-6 and IL-8 levels in the HF group than in group receiving MV alone. CONCLUSIONS: In a canine model of acute lung injury continuous HF improved cardiopulmonary function, reduced pulmonary edema, decreased lung permeability and inflammation, and decreased the plasma concentration of proinflammatory cytokines.

Albumins↗

PubMed2003

Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome.

KL-6 is a pulmonary epithelial mucin more prominently expressed on the surface membrane of alveolar type II cells when these cells are proliferating, stimulated, and/or injured. We hypothesized that high levels of KL-6 in epithelial lining fluid and plasma would reflect the severity of lung injury in patients with acute lung injury (ALI). Epithelial lining fluid was obtained at onset (day 0) and day 1 of acute respiratory distress syndrome (ARDS)/ALI by bronchoscopic microsampling procedure in 35 patients. On day 0, KL-6 and albumin concentrations in epithelial lining fluid were significantly higher than in normal controls (P < 0.001), and the concentrations of KL-6 in epithelial lining fluid (P < 0.002) and in plasma (P < 0.0001) were higher in nonsurvivors than in survivors of ALI/ARDS. These observations were corroborated by the immunohistochemical localization of KL-6 protein expression in the lungs of nonsurvivors with ALI and KL-6 secretion from cultured human alveolar type II cells stimulated by proinflammatory cytokines. Because injury to distal lung epithelial cells, including alveolar type II cells, is important in the pathogenesis of ALI, the elevation of KL-6 concentrations in plasma and epithelial lining fluid could be valuable indicators for poor prognosis in clinical ALI.

Adult↗

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

Functional identification of the alveolar edema reabsorption activity of murine tumor necrosis factor-alpha.

Tumor necrosis factor-alpha (TNF-alpha) activates sodium channels in Type II alveolar epithelial cells, an important mechanism for the reported fluid resorption capacity of the cytokine. Both TNF-alpha receptor-dependent and -independent effects were proposed for this activity in vitro, the latter mechanism mediated by the lectin-like domain of the molecule. In this study, the relative contribution of the receptor-dependent versus receptor-independent activities was investigated in an in situ mouse lung model and an ex vivo rat lung model. Fluid resorption due to murine TNF-alpha (mTNF-alpha) was functional in mice that were genetically deficient in both types of mTNF-alpha receptor, establishing the importance of mTNF-alpha receptor-independent effects in this species. In addition, we assessed the capacity of an mTNF-alpha-derived peptide (mLtip), which activates sodium transport by a receptor-independent mechanism, to reduce lung water content in an isolated, ventilated, autologous blood-perfused rat lung model. The results show that in this model, mLtip, in contrast to mTNF-alpha, produced a progressive recovery of dynamic lung compliance and airway resistance after alveolar flooding. There was also a significant reduction in lung water. These results indicate that the receptor-independent lectin-like domain of mTNF-alpha has a potential physiological role in the resolution of alveolar edema in rats and mice.

Amiloride↗

PubMed2003

Protein C and thrombomodulin in human acute lung injury.

Decreased circulating protein C and increased circulating thrombomodulin are markers of the prothrombotic, antifibrinolytic state associated with poor outcomes in sepsis but have not been measured in patients with ALI (acute lung injury)/ARDS (acute respiratory distress syndrome). We measured circulating and intra-alveolar protein C and thrombomodulin in 45 patients with ALI/ARDS from septic and nonseptic causes and correlated the levels with clinical outcomes. Plasma protein C levels were lower in ALI/ARDS compared with normal. Lower levels of protein C were associated with worse clinical outcomes, including death, fewer ventilator-free days, and more nonpulmonary organ failures, even when only patients without sepsis were analyzed. Levels of thrombomodulin in pulmonary edema fluid from ALI/ARDS patients were >10-fold higher than normal plasma and 2-fold higher than ALI/ARDS plasma. Higher edema fluid thrombomodulin levels were associated with worse clinical outcomes. The higher levels in edema fluid compared with plasma suggest local release of soluble thrombomodulin in the lung, possibly from a lung epithelial source. To determine whether lung epithelial cells can release thrombomodulin, A549 cells and primary isolates of human alveolar type II cells were exposed to H2O2 or inflammatory cytokines. Both epithelial cell types released thrombomodulin into the media. In summary, the protein C system is markedly disrupted in patients with ALI/ARDS from both septic and nonseptic causes. The protein C system may be a potential therapeutic target in patients with ALI/ARDS.

Acute Disease↗

PubMed2003

Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury.

The alveolar fibrinolytic system is altered in acute lung injury (ALI). Levels of the fibrinolytic protease inhibitor, plasminogen activator inhibitor-1 (PAI-1), are too low in bronchoalveolar lavage to address its prognostic significance. This study was performed to assess whether PAI-1 antigen in undiluted pulmonary edema fluid levels can identify patients with ALI and predict their outcome. PAI-1 antigen levels in both plasma and edema fluid were higher in ALI compared with hydrostatic edema, and edema fluid PAI-1 values identified those with ALI with high sensitivity and specificity. Both the high plasma and edema fluid PAI-1 antigen values were associated with a higher mortality rate and fewer days of unassisted ventilation in patients with ALI. Differences in PAI-1 activity were concordant with levels of PAI-1 antigen. Although the fibrin-derived alveolar D-dimer levels were strikingly similar in both groups, ALI patients had a higher relative proportion of D-monomer. In conclusion, PAI-1 levels in edema fluid and plasma identify those with ALI that have a poor prognosis. The data indicate that fibrin turnover in early ALI is a consequence of a rapid fibrinogen influx and fractional fibrinolytic inhibition.

Acute Disease↗

PubMed2003

Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group.

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are syndromes of acute respiratory failure that result from acute pulmonary edema and inflammation. The development of ALI/ARDS is associated with several clinical disorders including direct pulmonary injury from pneumonia and aspiration as well as indirect pulmonary injury from trauma, sepsis, and other disorders such as acute pancreatitis and drug overdose. Although mortality from ALI/ARDS has decreased in the last decade, it remains high. Despite two major advances in treatment, low VT ventilation for ALI/ARDS and activated protein C for severe sepsis (the leading cause of ALI/ARDS), additional research is needed to develop specific treatments and improve understanding of the pathogenesis of these syndromes. The NHLBI convened a working group to develop specific recommendations for future ALI/ARDS research. Improved understanding of disease heterogeneity through use of evolving biologic, genomic, and genetic approaches should provide major new insights into pathogenesis of ALI. Cellular and molecular methods combined with animal and clinical studies should lead to further progress in the detection and treatment of this complex disease.

Academies and Institutes↗

PubMed2003

Prevention of ventilator-associated pneumonia: an evidence-based systematic review.

BACKGROUND: Ventilator-associated pneumonia is a common cause of morbidity in critically ill patients. Interventions beneficial to the prevention of ventilator-associated pneumonia would therefore have a significant impact on the care of these patients. PURPOSE: To perform a literature review and synthesis of methods for prevention of ventilator-associated pneumonia. DATA SOURCES: MEDLINE (1966-2001), the Cochrane Library, and bibliographies of retrieved articles. STUDY SELECTION: Studies were required to be prospective and controlled in design and to evaluate clinically important or surrogate outcomes. Surrogate outcomes were required to have a direct link to clinically important outcomes supported by the literature. DATA EXTRACTION: Data on patients, definitions, study design, and outcomes were abstracted and graded by using preestablished criteria. DATA SYNTHESIS: The preventive practices with the strongest supportive evidence were semi-recumbent positioning, sucralfate instead of H2-antagonists for stress ulcer prophylaxis, and selective digestive tract decontamination. Aspiration of subglottic secretions and oscillating beds may be useful in select populations. There is no evidence to support specific methods of enteral feeding or increased frequency of ventilator circuitry changes. CONCLUSIONS: After evaluation of potential benefits and risks, the authors recommend considering several specific interventions to reduce the incidence of ventilator-associated pneumonia: semi-recumbent positioning in all eligible patients, sucralfate rather than H2-antagonists in patients at low to moderate risk for gastrointestinal tract bleeding, and aspiration of subglottic secretions and oscillating beds in select patient populations. Selective digestive tract decontamination is not recommended because routine use may increase antimicrobial resistance.

Anti-Bacterial Agents↗

PubMed2003

High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance.

Tidal volume reduction during mechanical ventilation reduces mortality in patients with acute lung injury and the acute respiratory distress syndrome. To determine the mechanisms underlying the protective effect of low tidal volume ventilation, we studied the time course and reversibility of ventilator-induced changes in permeability and distal air space edema fluid clearance in a rat model of ventilator-induced lung injury. Anesthetized rats were ventilated with a high tidal volume (30 ml/kg) or with a high tidal volume followed by ventilation with a low tidal volume of 6 ml/kg. Endothelial and epithelial protein permeability were significantly increased after high tidal volume ventilation but returned to baseline levels when tidal volume was reduced. The basal distal air space fluid clearance (AFC) rate decreased by 43% (P < 0.05) after 1 h of high tidal volume but returned to the preventilation rate 2 h after tidal volume was reduced. Not all of the effects of high tidal volume ventilation were reversible. The cAMP-dependent AFC rate after 1 h of 30 ml/kg ventilation was significantly reduced and was not restored when tidal volume was reduced. High tidal volume ventilation also increased lung inducible nitric oxide synthase (NOS2) expression and air space total nitrite at 3 h. Inhibition of NOS2 activity preserved cAMP-dependent AFC. Because air space edema fluid inactivates surfactant and reduces ventilated lung volume, the reduction of cAMP-dependent AFC by reactive nitrogen species may be an important mechanism of clinical ventilator-associated lung injury.

Acute Disease↗

PubMed2003

Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury.

Granulocyte macrophage-colony stimulating factor (GM-CSF) plays an important role in pulmonary homeostasis, with effects on both alveolar macrophages and alveolar epithelial cells. We hypothesized that overexpression of GM-CSF in the lung would protect mice from hyperoxic lung injury by limiting alveolar epithelial cell injury. Wild-type C57BL/6 mice and mutant mice in which GM-CSF was overexpressed in the lung under control of the SP-C promoter (SP-C-GM mice) were placed in >95% oxygen. Within 6 days, 100% of the wild-type mice had died, while 70% of the SP-C-GM mice remained alive after 10 days in hyperoxia. Histological assessment of the lungs at day 4 revealed less disruption of the alveolar wall in SP-C-GM mice compared to wild-type mice. The concentration of albumin in bronchoalveolar lavage fluid after 4 days in hyperoxia was significantly lower in SP-C-GM mice than in wild-type mice, indicating preservation of alveolar epithelial barrier properties in the SP-C-GM mice. Alveolar fluid clearance was preserved in SP-C-GM mice in hyperoxia, but decreased significantly in hyperoxia-exposed wild-type mice. Staining of lung tissue for caspase 3 demonstrated increased apoptosis in alveolar wall cells in wild-type mice in hyperoxia compared to mice in room air. In contrast, SP-C-GM mice exposed to hyperoxia demonstrated only modest increase in alveolar wall apoptosis compared to room air. Systemic treatment with GM-CSF (9 micro g/kg/day) during 4 days of hyperoxic exposure resulted in decreased apoptosis in the lungs compared to placebo. In studies using isolated murine type II alveolar epithelial cells, treatment with GM-CSF greatly reduced apoptosis in response to suspension culture. In conclusion, overexpression of GM-CSF enhances survival of mice in hyperoxia; this effect may be explained by preservation of alveolar epithelial barrier function and fluid clearance, at least in part because of reduction in hyperoxia-induced apoptosis of cells in the alveolar wall.

Animals↗

PubMed2003

Acute lung injury and the acute respiratory distress syndrome.

Although ALI/ARDS mortality rates have improved over the last several decades, they remain high, particularly in the geriatric patient population. Although considerable progress has been made in understanding the pathogenesis of the disease, a large number of promising treatments have proven unsuccessful. One exception has been in the area of ventilator management, where a strategy of protective ventilation with low tidal volumes has demonstrated a significant mortality benefit. Basic research continues to help advance our understanding of this complex syndrome and identify interesting new directions of investigation. The results of several large, randomized trials of new ventilatory and pharmacologic strategies currently underway may help identify successful methods of treating this important disease.

Age Factors↗