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Biomedical subjects

Michael A Matthay

Publications and source records attributed to Michael A Matthay.

At least 55 records · Page 3Linked to original sources
PubMed2005

Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial.

CONTEXT: In uncontrolled clinical studies, prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury. However, the effect of prone positioning on clinical outcomes in children is not known. OBJECTIVE: To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning. DESIGN, SETTING, AND PATIENTS: Multicenter, randomized, controlled clinical trial conducted from August 28, 2001, to April 23, 2004, of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning. Randomization was concealed and group assignment was not blinded. INTERVENTION: Patients were randomized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria, with those patients in the prone group being positioned within 4 hours of randomization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days, after which they were positioned supine. Both groups were treated using lung protective ventilator and sedation protocols, extubation readiness testing, and hemodynamic, nutrition, and skin care guidelines. MAIN OUTCOME MEASURE: Ventilator-free days to day 28. RESULTS: The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule. There were no differences in the number of ventilator-free days between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, -0.2 days; 95% CI, -3.6 to 3.2; P = .91). After controlling for age, Pediatric Risk of Mortality III score, direct vs indirect acute lung injury, and mode of mechanical ventilation at enrollment, the adjusted difference in ventilator-free days was 0.3 days (95% CI, -3.0 to 3.5; P = .87). There were no differences in the secondary end points, including proportion alive and ventilator-free on day 28 (P = .45), mortality from all causes (P>.99), the time to recovery of lung injury (P = .78), organ-failure-free days (P = .88), and cognitive impairment (P = .16) or overall functional health (P = .12) at hospital discharge or on day 28. CONCLUSION: Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury.

Adolescent↗
PubMed2005

Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cells.

Apoptosis of distal lung epithelial cells plays a pivotal role in the pathogenesis of acute lung injury. In this context, proteinases, either circulating or leukocyte-derived, may contribute to epithelial apoptosis and lung injury. We hypothesized that apoptosis of lung epithelial cells induced by leukocyte elastase is mediated via the proteinase activated receptor (PAR)-1. Leukocyte elastase, thrombin, and PAR-1-activating peptide, but not the control peptide, induced apoptosis in human airway and alveolar epithelial cells as assessed by increases in cytoplasmic histone-associated DNA fragments and TUNEL staining. These effects were largely prevented by a specific PAR-1 antagonist and by short interfering RNA directed against PAR-1. To ascertain the mechanism of epithelial apoptosis, we determined that PAR-1AP, thrombin, and leukocyte elastase dissipated mitochondrial membrane potential, induced translocation of cytochrome c to the cytosol, enhanced cleavage of caspase-9 and caspase-3, and led to JNK activation and Akt inhibition. In concert, these observations provide strong evidence that leukocyte elastase mediates apoptosis of human lung epithelial cells through PAR-1-dependent modulation of the intrinsic apoptotic pathway via alterations in mitochondrial permeability and by modulation of JNK and Akt.

Apoptosis↗
PubMed2005

Decreased expression of both the alpha1- and alpha2-subunits of the Na-K-ATPase reduces maximal alveolar epithelial fluid clearance.

Impaired epithelial sodium channel function predisposes to delayed resorption of pulmonary edema and more severe experimental lung injury, whereas even a small fraction of the normal Na-K-ATPase activity is thought to be sufficient to maintain normal ion transport. However, direct proof is lacking. Therefore, we studied baseline and cAMP stimulated alveolar fluid clearance (AFC) in mice with a 50% decrease in lung protein expression of the alpha(1)- and/or alpha(2)-subunit of the Na-K-ATPase. There was no difference in basal and stimulated AFC in alpha(1)(+/-) or alpha(2)(+/-) mice compared with wild-type littermates. Also, the compound heterozygous mice (alpha(1)(+/-)/alpha(2)(+/-)) had normal basal AFC. However, the combined alpha(1)(+/-)/alpha(2)(+/-) mice showed a significant decrease in cAMP-stimulated AFC compared with wild-type littermates (11.1 +/- 1.0 vs. 14.9 +/- 1.8%/30 min, P < 0.001). When exposed to 96 h of >95% hyperoxia, the decrease in stimulated AFC in the alpha(1)(+/-)/alpha(2)(+/-) mice was not associated with more lung edema compared with wild-type littermates (lung wet-to-dry weight ratio 6.6 +/- 0.9 vs. 5.9 +/- 1.1, respectively; P = not significant). Thus a 50% decrease in protein expression of the alpha(1)- or alpha(2)-subunits of the Na-K-ATPase does not impair basal or stimulated AFC. However, a 50% protein reduction in both the alpha(1)- and alpha(2)-subunits of the Na-K-ATPase produces a submaximal stimulated AFC, suggesting a synergistic role for alpha(1)- and alpha(2)-subunits in cAMP-dependent alveolar epithelial fluid clearance.

Animals↗
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↗
PubMed2005

Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis.

PURPOSE: To assess the efficacy of subglottic secretion drainage in preventing ventilator-associated pneumonia. METHODS: We performed a comprehensive, systematic meta-analysis of randomized trials that have compared subglottic secretion drainage with standard endotracheal tube care in mechanically ventilated patients. Studies were identified by a computerized database search, review of bibliographies, and expert consultation. Summary risk ratios or weighted mean differences with 95% confidence intervals were calculated for each outcome using a fixed-effects model. RESULTS: Of 110 studies retrieved, five met the inclusion criteria and enrolled 896 patients. Subglottic secretion drainage reduced the incidence of ventilator-associated pneumonia by nearly half (risk ratio [RR] = 0.51; 95% confidence interval [CI]: 0.37 to 0.71), primarily by reducing early-onset pneumonia (pneumonia occurring within 5 to 7 days after intubation). Although significant heterogeneity was found for several endpoints, this was largely resolved by excluding a single outlying study. In the remaining four studies, which recruited patients expected to require >72 hours of mechanical ventilation, secretion drainage shortened the duration of mechanical ventilation by 2 days (95% CI: 1.7 to 2.3 days) and the length of stay in the intensive care unit by 3 days (95% CI: 2.1 to 3.9 days), and delayed the onset of pneumonia by 6.8 days (95% CI: 5.5 to 8.1 days). CONCLUSION: Subglottic secretion drainage appears effective in preventing early-onset ventilator-associated pneumonia among patients expected to require >72 hours of mechanical ventilation.

Confidence Intervals↗
PubMed2005

Recent advances in mechanical ventilation.

Important advances have been made over the past decade towards understanding the optimal approach to ventilating patients with acute respiratory failure. Evidence now supports the use of noninvasive positive pressure ventilation in selected patients with hypercapnic respiratory failure and chronic obstructive pulmonary disease, cardiogenic pulmonary edema, and for facilitating the discontinuation of ventilatory support in patients with chronic pulmonary disease. The concept of a lung protective ventilatory strategy has revolutionized the management of the acute respiratory distress syndrome. The process of liberation from mechanical ventilation is becoming more standardized, with evidence supporting daily trials of spontaneous breathing in all suitable mechanically ventilated patients. This article critically reviews the most important recent advances in mechanical ventilation and suggests future directions for further research in the field.

Acute Disease↗
PubMed2005

High prevalence of pulmonary arterial thrombi in donor lungs rejected for transplantation.

BACKGROUND: Donor hypoxemia is a common reason for the rejection of lungs for transplantation. Organ donors are at high risk for venous thromboembolism. Pulmonary arterial thrombosis could contribute to donor hypoxemia. The primary objective of this study was to prospectively quantify the incidence of pulmonary arterial thrombosis in organ donors whose lungs were rejected for transplantation. The secondary objective was to better define the spectrum of histologic abnormalities in the same group of lungs. METHODS: A complete gross pathologic and histologic analysis of whole lung specimens was done on lungs from 17 donors whose lungs were rejected for transplantation. Lungs had not been flushed with a pulmonary preservation solution. RESULTS: Overall, 35% of the donors had gross or microscopic evidence of either pulmonary arterial thrombosis, pulmonary infarction, or both. Clinical characteristics, including oxygenation, were not significantly different between donors who had thrombi or infarction and donors who did not. Other pathologic findings included bronchopneumonia (focal or early in 4/17, moderate or severe in 8/17), respiratory bronchiolitis (7/17) and centriacinar emphysema (7/17). CONCLUSIONS: Pulmonary arterial thrombosis and/or pulmonary infarction are very common in organ donors whose lungs are rejected for transplantation and might contribute to lung dysfunction both in lung donors and lung recipients. Further studies are needed to define the incidence of pulmonary arterial thrombosis in organ donors whose lungs are used for transplantation and to better assess the adverse clinical consequences of donor pulmonary arterial thrombosis in lung recipients.

Adult↗
PubMed2005

Acute effects of tidal volume strategy on hemodynamics, fluid balance, and sedation in acute lung injury.

OBJECTIVE: To examine the effects of mechanical ventilation with a tidal volume of 6 mL/kg compared with 12 mL/kg predicted body weight on hemodynamics, vasopressor use, fluid balance, diuretics, sedation, and neuromuscular blockade within 48 hrs in patients with acute lung injury and acute respiratory distress syndrome. DESIGN: Retrospective analysis of a previously conducted randomized, clinical trial. SETTING: Two adult intensive care units at a tertiary university medical center and a large county hospital. PATIENTS: One hundred eleven patients who were enrolled in the National Institutes of Health ARDS Network trial at the University of California, San Francisco. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Compared with 12 mL/kg predicted body weight, treatment with a tidal volume of 6 mL/kg predicted body weight had no adverse effects on hemodynamics. There were also no differences in the need for supportive therapies, including vasopressors, intravenous fluids, or diuretics. In addition, there were no differences in body weight, urine output, and fluid balance. Finally, there was no difference in the need for sedation or neuromuscular blockade between the two tidal volume protocols. CONCLUSIONS: When compared with ventilation with 12 mL/kg predicted body weight, patients treated with the lung-protective 6 mL/kg predicted body weight tidal volume protocol had no difference in their supportive care requirements. Therefore, concerns regarding potential adverse effects of this protocol should not preclude its use in patients with acute lung injury or the acute respiratory distress syndrome.

Adult↗
PubMed2005

Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury.

OBJECTIVES: To evaluate the association between interleukin-6, interleukin-8, and interleukin-10 and clinical outcomes including mortality in patients with acute lung injury and to determine whether lower tidal volume ventilation was associated with a decrease in plasma cytokines in patients with acute lung injury. DESIGN: Multiple-center, randomized trial. SETTING: Intensive care units in ten university centers. PATIENTS: The study included 861 patients enrolled in the National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for acute lung injury. INTERVENTIONS: Patients were randomized to a 6 mL/kg or a 12 mL/kg tidal volume strategy that has been previously described. MEASUREMENTS AND MAIN RESULTS: Baseline plasma levels of interleukin-6, interleukin-8, and interleukin-10 were each associated with an increased risk of death in both logistic regression analyses controlling for ventilator group (odds ratio 1.63 per log-10 increment, 95% confidence interval 1.33-1.98; odds ratio 2.33 per log-10 increment, 95% confidence interval 1.79-3.03; odds ratio 2.02 per log-10 increment, 95% confidence interval 1.47-2.76, respectively) and multivariate analyses controlling for ventilation strategy, Acute Physiology and Chronic Health Evaluation III score, Pao2/Fio2 ratio, creatinine, platelet count, and vasopressor use (odds ratio 1.63 per log-10 increment, 95% confidence interval 0.93-1.49; odds ratio 1.73 per log-10 increment, 95% confidence interval 1.29-2.34; odds ratio 1.23 per log-10 increment, 95% confidence interval 0.86-1.76, respectively). Interleukin-6 and interleukin-8 levels were also associated with a significant decrease in ventilator free and organ failure free days. Patients with sepsis had the highest cytokine levels and the greatest risk of death per cytokine elevation. By day 3, the 6 mL/kg strategy was associated with a greater decrease in interleukin-6 and interleukin-8 levels. There was a 26% reduction in interleukin-6 (95% confidence interval, 12-37%) and a 12% reduction in interleukin-8 (95% confidence interval, 1-23%) in the 6 mL/kg group compared with the 12 mL/kg group. CONCLUSIONS: In patients with acute lung injury, plasma interleukin-6 and interleukin-8 levels are associated with morbidity and mortality. The severity of inflammation varies with clinical risk factor, suggesting that clinical risk factor should be considered when both developing and testing therapeutic interventions. Low tidal volume ventilation is associated with a more rapid attenuation of the inflammatory response.

APACHE↗
PubMed2005

Differential effects of sustained inflation recruitment maneuvers on alveolar epithelial and lung endothelial injury.

OBJECTIVE: The role of recruitment maneuvers in mechanical ventilation for patients with the acute respiratory distress syndrome and acute lung injury remains uncertain in part due to a lack of data on the effects of specific recruitment maneuvers on lung injury severity. The primary objective of this study was to determine the effect of one type of recruitment maneuver--sustained inflation--on alveolar epithelial and lung endothelial injury in experimental acute lung injury. DESIGN: Randomized experimental study. SETTING: Academic research laboratory. SUBJECTS: Forty-nine Sprague-Dawley rats. INTERVENTIONS: Lung injury was induced in anesthetized, ventilated rats by instillation of acid (pH 1.5) into the airspaces. Rats were ventilated with a tidal volume of 6 mL/kg and a positive end-expiratory pressure of 5 cm H(2)O with or without a sustained inflation recruitment maneuver repeated every 30 mins. Each recruitment maneuver consisted of two 30-sec inflations to total lung capacity (30 cm H(2)O) 1 min apart. MEASUREMENTS AND MAIN RESULTS: The use of recruitment maneuvers significantly improved oxygenation, compliance, end-expiratory lung volume, functional residual capacity, and deadspace fraction. Recruitment maneuvers reduced extravascular lung water and lung endothelial injury as measured by protein permeability (217 +/- 28 vs. 314 +/- 70 extravascular plasma equivalents [microL], p < .05). However, recruitment maneuvers did not prevent alveolar epithelial injury. Epithelial permeability and bronchoalveolar lavage RTI40 levels, a marker of type I cell injury, were similar with or without recruitment maneuvers. Recruitment maneuvers decreased epithelial fluid transport, a functional marker of epithelial injury. Recruitment maneuvers did not reduce markers of airspace inflammation. CONCLUSIONS: Sustained inflation recruitment maneuvers improve respiratory mechanics and oxygenation and may protect the lung endothelium but do not reduce alveolar epithelial injury. Because of the differential effects of recruitment maneuvers on the lung endothelium and alveolar epithelium, the net effect in clinical acute lung injury may not be beneficial. Additional clinical studies will be needed to assess the net impact of recruitment maneuvers in patients with acute lung injury.

Animals↗
PubMed2005

Alveolar epithelium: role in lung fluid balance and acute lung injury.

The resolution of alveolar edema is regulated by active sodium and chloride transport across the pulmonary epithelium, including alveolar epithelial type I and II cells as well as distal airway epithelia. Catecholamine-dependent mechanisms can markedly upregulate alveolar fluid clearance even under pathological conditions, an effect that is mediated by both epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR). Under pathological conditions, impaired alveolar fluid clearance is associated with worse survival in patients with acute lung injury. However, there is some experimental and clinical evidence that cAMP stimulation could accelerate the resolution of pulmonary edema in the presence of acute lung injury. Clinical trials are needed to test this potential therapeutic strategy in patients with acute lung injury.

Animals↗
PubMed2005

Is there a role for beta-adrenoceptor agonists in the management of acute lung injury and the acute respiratory distress syndrome?

Despite improvements in general supportive care and ventilatory strategies designed to limit lung injury, no specific pharmacological therapy has yet proven to be efficacious in the management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Based on experimental studies, as well as studies of the ex-vivo human lung, pulmonary edema fluid clearance from the alveolar space can be augmented by both inhaled and systemic beta2-adrenoceptor agonists (beta2-agonists). Additionally, in the presence of lung injury, beta2-agonists may reduce lung vascular permeability. Treatment with beta2-agonists may also increase the secretion of surfactant and have anti-inflammatory effects. In view of these potentially beneficial effects, beta2-agonist therapy should be evaluated for the treatment of lung injury in humans, particularly because they are already in wide clinical use and do not seem to have serious adverse effects in critically ill patients.

Adrenergic beta-Agonists↗
PubMed2005

Accuracy of physiologic dead space measurements in patients with acute respiratory distress syndrome using volumetric capnography: comparison with the metabolic monitor method.

BACKGROUND: Volumetric capnography is an alternative method of measuring expired carbon dioxide partial pressure (P(eCO2)) and physiologic dead-space-to-tidal-volume ratio (V(D)/V(T)) during mechanical ventilation. In this method, P(eCO2) is measured at the Y-adapter of the ventilator circuit, thus eliminating the effects of compression volume contamination and the need to apply a correction factor. We investigated the accuracy of volumetric capnography in measuring V(D)/V(T), compared to both uncorrected and corrected measurements, using a metabolic monitor in patients with acute respiratory distress syndrome (ARDS). METHODS: There were 90 measurements of V(D)/V(T) made in 23 patients with ARDS. The P(eCO2) was measured during a 5-min expired-gas collection period with a Delta-trac metabolic monitor, and was corrected for compression volume contamination using a standard formula. Simultaneous measurements of P(eCO2) and V(D)/V(T) were obtained using volumetric capnography. RESULTS: V(D)/V(T) measured by volumetric capnography was strongly correlated with both the uncorrected (r2 = 0.93, p < 0.0001) and corrected (r2 = 0.89, p < 0.0001) measurements of V(D)/V(T) made using the metabolic monitor technique. Measurements of V(D)/V(T) made with volumetric capnography had a bias of 0.02 and a precision of 0.05 when compared to the V(D)/V(T) corrected for estimated compression volume contamination. CONCLUSION: Volumetric capnography measurements of V(D)/V(T) in mechanically-ventilated patients with ARDS are as accurate as those obtained by metabolic monitor technique. .

Adult↗
PubMed2004

Pediatric acute lung injury: prospective evaluation of risk factors associated with mortality.

RATIONALE: The 1994 American European Consensus Committee definitions of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) have not been applied systematically in the pediatric population. OBJECTIVES: The purpose of this study was to evaluate prospectively the epidemiology and clinical risk factors associated with death and prolonged mechanical ventilation in all pediatric patients admitted to two large, pediatric intensive care units with ALI/ARDS using Consensus criteria. METHODS: All pediatric patients meeting Consensus Committee definitions for ALI were prospectively identified and included in a relational database. MEASUREMENTS AND MAIN RESULTS: There were 328 admissions for ALI/ARDS with a mortality of 22%. Multivariate logistic regression analyses revealed (1) the initial severity of oxygenation defect, as measured by the Pa(O2)/FI(O2) ratio; (2) the presence of nonpulmonary and non-central nervous system (CNS) organ dysfunction; and (3) the presence of CNS dysfunction were independently associated with mortality and prolonged mechanical ventilation. A substantial fraction of patients (28%) did not require mechanical ventilation at the onset of ALI; 46% of these patients eventually required intubation for worsening ALI. CONCLUSIONS: Mortality in pediatric ALI/ARDS is high and several risk factors have major prognostic value. In contrast to ALI/ARDS in adults, the initial severity of arterial hypoxemia in children correlates well with mortality. A significant fraction of patients with pediatric ALI/ARDS can be identified before endotracheal intubation is required. These patients provide a valuable group in whom new therapies can be tested.

Adolescent↗
PubMed2004

Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury.

Ventilator-induced lung injury (VILI) is an inflammatory process that can be attenuated by lung protective ventilation strategies. Our objectives to further investigate the pathogenesis of ALI and VILI and the mechanism of lung protection in these syndromes were: 1) to determine if plasma measurements of soluble TNF receptor I (sTNFRI) and II (sTNFRII) would predict the development of ALI and mortality in a small single center trial; 2) to test the predictive value of these markers and of TNF-alpha in a larger, broader group of patients with ALI; 3) to test the hypothesis that low tidal volume ventilation (LTVV) would be associated with a decrease in plasma levels of TNF-alpha, sTNFRI, and sTNFRII. In the single center study, sTNFRI and II levels were higher in patients at risk for and with ALI, but they did not predict the development of the syndrome. In the multicenter trial sTNFRI and II were strongly associated with mortality (OR 5.76/1 log10 increment in receptor level; 95% CI 2.63-12.6 and OR 2.58; 95% CI 1.05-6.31, respectively) and morbidity measured as fewer nonpulmonary organ failure-free and ventilator-free days. The LTVV strategy was associated with an attenuation of plasma sTNFRI levels. In vitro, stimulated A549 cells release sTNFRI but not sTNRFII. In conclusion, plasma levels of sTNFRI and II can serve as biomarkers for morbidity and mortality in patients with ALI. Furthermore, LTVV is associated with a specific decrease in sTNFRI levels. This suggests that one beneficial effect of LTVV may be to attenuate alveolar epithelial injury.

Acute Disease↗
PubMed2004

Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock.

In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LPS activation of epithelial cells to levels measured with "septic" plasma, whereas soluble MD-2-depleted plasma lost its effects. The same "MD-2 activity" was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LPS but were not able to mediate LPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis.

Antigens, Surface↗