Showing papers by "Michael A. Matthay published in 2008"

Intensity of renal support in critically ill patients with acute kidney injury

Abstract: We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. Results Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P = 0.47). There was no significant difference between the two groups in the duration of renalreplacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. Conclusions Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury

Abstract: Objectives: To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and outcomes of acute lung injury, and whether plasma RAGE levels are affected by lower tidal volume ventilation. Design, setting and participants: Measurement of plasma RAGE levels from 676 subjects enrolled in a large randomised controlled trial of lower tidal volume ventilation in acute lung injury. Measurements and main results: Higher baseline plasma RAGE was associated with increased severity of lung injury. In addition, higher baseline RAGE was associated with increased mortality (OR for death 1.38 (95% CI 1.13 to 1.68) per 1 log increment in RAGE; p = 0.002) and fewer ventilator free and organ failure free days in patients randomised to higher tidal volumes. These associations persisted in multivariable models that adjusted for age, gender, severity of illness and the presence of sepsis or trauma. Plasma RAGE was not associated with outcomes in the lower tidal volume group (p = 0.09 for interaction in unadjusted analysis). In both tidal volume groups, plasma RAGE levels declined over the first 3 days; however, the decline was 15% greater in the lower tidal volume group (p = 0.02; 95% CI 2.4% to 25.0%). Conclusions: Baseline plasma RAGE levels are strongly associated with clinical outcomes in patients with acute lung injury ventilated with higher tidal volumes. Lower tidal volume ventilation may be beneficial in part by decreasing injury to the alveolar epithelium.

Randomized clinical trial of activated protein C for the treatment of acute lung injury.

Abstract: Rationale: Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung ...

Interleukin-1β Causes Acute Lung Injury via αvβ5 and αvβ6 Integrin–Dependent Mechanisms

Abstract: Interleukin (IL)-1beta has previously been shown to be among the most biologically active cytokines in the lungs of patients with acute lung injury (ALI). Furthermore, there is experimental evidence that lung vascular permeability increases after short-term exposure to IL-1 protein, although the exact mechanism is unknown. Therefore, the objective of this study was to determine the mechanisms of IL-1beta-mediated increase in lung vascular permeability and pulmonary edema following transient overexpression of this cytokine in the lungs by adenoviral gene transfer. Lung vascular permeability increased with intrapulmonary IL-1beta production with a maximal effect 7 days after instillation of the adenovirus. Furthermore, inhibition of the alphavbeta6 integrin and/or transforming growth factor-beta attenuated the IL-1beta-induced ALI. The results of in vitro studies indicated that IL-1beta caused the activation of transforming growth factor-beta via RhoA/alphavbeta6 integrin-dependent mechanisms and the inhibition of the alphavbeta6 integrin and/or transforming growth factor-beta signaling completely blocked the IL-1beta-mediated protein permeability across alveolar epithelial cell monolayers. In addition, IL-1beta increased protein permeability across lung endothelial cell monolayers via RhoA- and alphavbeta5 integrin-dependent mechanisms. The final series of in vivo experiments demonstrated that pretreatment with blocking antibodies to both the alphavbeta5 and alphavbeta6 integrins had an additive protective effect against IL-1beta-induced ALI. In summary, these results demonstrate a critical role for the alphavbeta5/beta6 integrins in mediating the IL-1beta-induced ALI and indicate that these integrins could be a potentially attractive therapeutic target in ALI.

Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury

Abstract: Acute lung injury (ALI) is a major cause of acute respiratory failure with high mortality despite lung-protective ventilation. Prior work has shown disordered inflammation and coagulation in ALI, with strong correlations between biomarker abnormalities and worse clinical outcomes. We measured plasma markers of inflammation, coagulation and fibrinolysis simultaneously to assess whether these markers remain predictive in the era of lung-protective ventilation. Plasma samples and ventilator data were prospectively collected from 50 patients with early ALI. Plasma biomarkers of inflammation (IL-6, IL-8, intercellular adhesion molecule 1), of coagulation (thrombomodulin, protein C) and of fibrinolysis (plasminogen activator inhibitor 1) were measured by ELISA. Biomarker levels were compared between survivors (n = 29) and non-survivors (n = 21) using Mann–Whitney analysis. The tidal volume for the study group was 6.6 ± 1.1 ml/kg predicted body weight and the plateau pressure was 25 ± 7 cmH2O (mean ± standard deviation), consistent with lung-protective ventilation. All markers except IL-6 were significantly different between survivors and nonsurvivors. Nonsurvivors had more abnormal values. Three biomarkers – IL-8, intercellular adhesion molecule 1 and protein C – remained significantly different by multivariate analysis that included age, gender, Simplified Acute Physiology Score II and all biomarkers that were significant on bivariate analysis. Higher levels of IL-8 and intercellular adhesion molecule 1 were independently predictive of worse outcomes (odds ratio = 2.0 and 5.8, respectively; P = 0.04 for both). Lower levels of protein C were independently associated with an increased risk of death (odds ratio = 0.5), a result that nearly reached statistical significance (P = 0.06). Despite lung-protective ventilation, abnormalities in plasma levels of markers of inflammation, coagulation and fibrinolysis predict mortality in ALI patients, indicating more severe activation of these biologic pathways in nonsurvivors.

Predictors of mortality in acute lung injury during the era of lung protective ventilation

Abstract: Background: Lung protective ventilation has been widely adopted for the management of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Consequently, ventilator associated lung injury and mortality have decreased. It is not known if this ventilation strategy changes the prognostic value of previously identified demographic and pulmonary predictors of mortality, such as respiratory compliance and the arterial oxygen tension to inspired oxygen fraction ratio (Pao 2 /Fio 2 ). Methods: Demographic, clinical, laboratory and pulmonary variables were recorded in 149 patients with ALI/ARDS. Significant predictors of mortality were identified in bivariate analysis and these were entered into multivariate analysis to identify independent predictors of mortality. Results: Hospital mortality was 41%. In the bivariate analysis, 17 variables were significantly correlated with mortality, including age, APACHE II score and the presence of cirrhosis. Pulmonary parameters associated with death included Pao 2 /Fio 2 and oxygenation index ((mean airway pressure×Fio 2 ×100)÷Pao 2 ). In unadjusted analysis, the odds ratio (OR) of death for Pao 2 /Fio 2 was 1.57 (CI 1.12 to 3.04) per standard deviation decrease. However, in adjusted analysis, Pao 2 /Fio 2 was not a statistically significant predictor of death, with an OR of 1.29 (CI 0.82 to 2.02). In contrast, oxygenation index (OI) was a statistically significant predictor of death in both unadjusted analysis (OR 1.89 (CI 1.28 to 2.78)) and in adjusted analysis (OR 1.84 (CI 1.13 to 2.99)). Conclusions: In this cohort of patients with ALI/ARDS, OI was an independent predictor of mortality, whereas Pao 2 /Fio 2 was not. OI may be a superior predictor because it integrates both airway pressure and oxygenation into a single variable.

Advances in Critical Care for the Nephrologist: Acute Lung Injury/ARDS

Abstract: Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are a major cause of acute respiratory failure in the critically ill patient. ALI and ARDS are characterized by the acute onset of severe hypoxemia and bilateral pulmonary infiltrates in the absence of clinical evidence for left atrial hypertension. These conditions are differentiated from one another by the ratio of the partial pressure of oxygen in the arterial blood to the inspired fraction of oxygen; ARDS requires a more severe oxygenation defect. ALI and ARDS may occur in association with a number of clinical disorders, including sepsis, pneumonia, aspiration, trauma including inhalational injury, and blood transfusions. The mortality rate remains high, in the range of 25% to 40%. The pathophysiology of ALI/ARDS involves resident lung cells, including endothelial and epithelial cells, as well as neutrophils, monocytes/macrophages, and platelets. When ALI/ARDS is complicated by acute kidney injury, mortality increases substantially. Several supportive and pharmacologic therapies have been tested in clinical trials. Of these, a low tidal volume, lung protective ventilation strategy is the only strategy that has been demonstrated in a large, multicenter randomized clinical trial to reduce mortality for patients with ALI/ARDS. Based on a recent randomized trial, a conservative fluid management strategy reduces the duration of mechanical ventilation without increasing the incidence of renal failure. Pharmacologic strategies and other ventilator management strategies have not been successful to date; however, several randomized, placebo controlled treatment trials are ongoing.

CD47 Deficiency Protects Mice from Lipopolysaccharide-Induced Acute Lung Injury and Escherichia coli Pneumonia

Abstract: CD47 modulates neutrophil transmigration toward the sites of infection or injury. Mice lacking CD47 are susceptible to Escherichia coli (E. coli) peritonitis. However, less is known concerning the role of CD47 in the development of acute lung inflammation and injury. In this study, we show that mice lacking CD47 are protected from LPS-induced acute lung injury and E. coli pneumonia with a significant reduction in pulmonary edema, lung vascular permeability, and bacteremia. Reconstitution of CD47(+/-) mice with CD47(-/-) neutrophils significantly reduced lung edema and neutrophil infiltration, thus demonstrating that CD47(+) neutrophils are required for the development of lung injury from E. coli pneumonia. Importantly, CD47-deficient mice with E. coli pneumonia had an improved survival rate. Taken together, deficiency of CD47 protects mice from LPS-induced acute lung injury and E. coli pneumonia. Targeting CD47 may be a novel pathway for treatment of acute lung injury.

Prostaglandin E2 Mediates IL-1β-Related Fibroblast Mitogenic Effects in Acute Lung Injury through Differential Utilization of Prostanoid Receptors

Abstract: The fibroproliferative response to acute lung injury (ALI) results in severe, persistent respiratory dysfunction. We have reported that IL-1beta is elevated in pulmonary edema fluid in those with ALI and mediates an autocrine-acting, fibroblast mitogenic pathway. In this study, we examine the role of IL-1beta-mediated induction of cyclooxygenase-2 and PGE2, and evaluate the significance of individual E prostanoid (EP) receptors in mediating the fibroproliferative effects of IL-1beta in ALI. Blocking studies on human lung fibroblasts indicate that IL-1beta is the major cyclooxygenase-2 mRNA and PGE2-inducing factor in pulmonary edema fluid and accounts for the differential PGE2 induction noted in samples from ALI patients. Surprisingly, we found that PGE2 produced by IL-1beta-stimulated fibroblasts enhances fibroblast proliferation. Further studies revealed that the effect of fibroblast proliferation is biphasic, with the promitogenic effect of PGE2 noted at concentrations close to that detected in pulmonary edema fluid from ALI patients. The suppressive effects of PGE2 were mimicked by the EP2-selective receptor agonist, butaprost, by cAMP activation, and were lost in murine lung fibroblasts that lack EP2. Conversely, the promitogenic effects of mid-range concentrations of PGE2 were mimicked by the EP3-selective agent, sulprostone, by cAMP reduction, and lost upon inhibition of Gi-mediated signaling with pertussis toxin. Taken together, these data demonstrate that PGE2 can stimulate or inhibit fibroblast proliferation at clinically relevant concentrations, via preferential signaling through EP3 or EP2 receptors, respectively. Such mechanisms may drive the fibroproliferative response to ALI.

Intra-alveolar tissue factor pathway inhibitor is not sufficient to block tissue factor procoagulant activity.

Abstract: The alveolar compartment in acute lung injury contains high levels of tissue factor (TF) procoagulant activity favoring fibrin deposition. We previously reported that the alveolar epithelium can re...

Treatment of acute lung injury: clinical and experimental studies.

Abstract: This presentation at the 2007 Aspen Lung Injury and Repair Conference provided a brief historical perspective from the 1998 Aspen Conference on Acute Lung Injury, highlighting the discussion of clinical definitions. There was also a review of the National Heart, Lung, and Blood Institute ARDS Network clinical trials, with an emphasis on the success of the lung-protective ventilation strategy in reducing mortality. In addition, there was a discussion of the recently completed fluid and catheter treatment trial, which demonstrated no benefit for pulmonary arterial catheterization over central venous catheterization for monitoring patients with acute lung injury (ALI). The trial demonstrated an increase in ventilator-free days with a fluid-conservative protocol. Finally, there was a discussion of recent experimental studies that show promise for cell-based therapy with mesenchymal stem cells for the treatment of endotoxin-induced ALI in mice. There were three objectives for this presentation at the 2007 Lung Injury, Repair, and Remodeling Conference: (1) to provide a brief historical perspective from the 1998 Aspen Conference on Acute Lung Injury; (2) to review major National Heart, Lung, and Blood Institute clinical trials conducted in the past 10 years by the ARDS Network; and (3) to review some of our promising work with cell-based therapy for experimental ALI.

Bone Marrow-Derived Cells Participate in Stromal Remodeling of the Lung Following Acute Bacterial Pneumonia in Mice

Abstract: Bone marrow-derived cells (BMDC) have been shown to graft injured tissues, differentiate in specialized cells, and participate in repair. The importance of these processes in acute lung bacterial inflammation and development of fibrosis is unknown. The goal of this study was to investigate the temporal sequence and lineage commitment of BMDC in mouse lungs injured by bacterial pneumonia. We transplanted GFP-tagged BMDC into 5-Gy-irradiated C57BL/6 mice. After 3 months of recovery, mice were subjected to LD(50) intratracheal instillation of live E. coli (controls received saline) which produced pneumonia and subsequent areas of fibrosis. Lungs were investigated by immunohistology for up to 6 months. At the peak of lung inflammation, the predominant influx of BMDC were GFP(+) leukocytes. Postinflammatory foci of lung fibrosis were evident after 1-2 months. The fibrotic foci in lung stroma contained clusters of GFP(+) CD45(+) cells, GFP(+) vimentin-positive cells, and GFP(+) collagen I-positive fibroblasts. GFP(+) endothelial or epithelial cells were not identified. These data suggest that following 5-Gy irradiation and acute bacterial pneumonia, BMDC may temporarily participate in lung postinflammatory repair and stromal remodeling without long-term engraftment as specialized endothelial or epithelial cells.

Alterations in the proteome of pulmonary alveolar type II cells in the rat after hepatic ischemia-reperfusion

Abstract: Objective: Hepatic ischemia-reperfusion can be associated with acute lung injury. Alveolar epithelial type II cells (ATII) play an important role in maintaining lung homeostasis in acute lung injury. Design: To study potentially new mechanisms of hepatic ischemia-reperfusion-induced lung injury, we examined how liver ischemia-reperfusion altered the proteome of ATII. Setting: Laboratory investigation. Subjects: Spontaneously breathing male Zucker rats. Interventions: Rats were anesthetized with isoflurane. The vascular supply to the left and medial lobe of the liver was clamped for 75 mins and then reperfused. Sham-operated rats were used as controls. After 8 hrs, rats were killed. Measurements and Main Results: Bronchoalveolar lavage and differential cell counts were performed, and tumor necrosis factor- and cytokine-induced neutrophil chemotactic factor-1 in plasma were determined by enzyme-linked immunosorbent assay. ATII were isolated, lysed, tryptically digested, and labeled using isobaric tags (iTRAQ). The samples were fractionated by cation exchange chromatography, separated by high-performance liquid-chromatography, and identified using electrospray tandem mass spectrometry. Spectra were interrogated and quantified using ProteinProspector. Quantitative proteomics provided quantitative data for 94 and 97 proteins in the two groups. Significant changes in ATII protein content included 30% to 40% increases in adenosine triphosphate synthases, adenosine triphosphate/adenosine diphosphate translocase, and catalase (all p < .001). Following liver ischemia-reperfusion, there was also a significant increase in the percentage of neutrophils in bronchoalveolar lavage (48% 26%) compared with sham-operated controls (5% 3%) (p < .01), and plasma tumor necrosis factor- levels were also significantly increased. Conclusions: The proteins identified by quantitative proteomics indicated significant changes in moderators of cell metabolism and host defense in ATII. These findings provide new insights into possible mechanisms responsible for hepatic ischemiareperfusion-related acute lung injury and suggest that ATII cells in the lung sense and respond to hepatic injury. (Crit Care Med 2008; 36:1846‐1854)

Measurement of extravascular lung water in patients with pulmonary edema.

Abstract: measurement of extravascular lung water has been a topic of major interest for more than two decades ([1][1], [5][2], [19][3]). In the recent article by Effros et al. ([2][4]), they provide a review of current and past efforts to measure extravascular lung water with thermal and osmotic dilution

Novel molecular strategy to prevent pulmonary edema.

Abstract: Alveolar fluid clearance, the capacity to resolve alveolar edema, depends on active sodium and chloride transport (1, 2). Several clinical studies have indicated that alveolar fluid clearance is impaired in patients with acute lung injury (3–5). Therefore, there has been a major interest in identifying mechanisms that could up-regulate the rate of alveolar fluid clearance and enhance the resolution of pulmonary edema in patients with acute lung injury. Both cyclic adenosine monophosphate (cAMP)-dependent and independent pathways have been identified that can increase the rate of alveolar fluid clearance and the resolution of pulmonary edema (1, 2, 6). In this issue of Critical Care Medicine, Vadasz et al. (13) provide evidence that the lectin-like domain of tumor necrosis factor (TNF)-α (TIP) can decrease pulmonary edema in an isolated, ventilated, and buffer-perfused rabbit lung preparation. The authors induced hydrostatic edema and in another group of experiments they created an increased permeability lung edema with endotoxin. In both models, they found that pretreatment with TIP decreased lung edema by both attenuating microvascular permeability as well as preventing an increase in the epithelial lining fluid volume. Although the mechanism for the absence of an increase of lung edema is not completely resolved, the results suggest that TIP may increase edema fluid clearance through activation of the Na,KATPase pump by promoting Na,KATPase pump exocytosis to the basolateral alveolar epithelial surface. This increase in activity of the Na,KATPase pump could lead to an increase in the amiloride-sensitive sodium transport across the apical surface of alveolar epithelial type II cells. Although TNF-α is known to potentially increase inflammatory lung injury through several pathways, prior experimental work suggested that TNF might modulate alveolar fluid clearance. Approximately 10 years ago, Rezaiguia et al. (7) reported that alveolar fluid clearance was increased in a tumor necrosis TNF-α dependent manner in a Pseudomonas aeruginosa pneumonia model in rats. These observations were confirmed by another group of investigators who found that TNF-α increased alveolar fluid clearance in a rat model of intestinal ischemia-reperfusion injury (8). However, it has also been observed by another research group that TNF-α could down-regulate αENaC gene expression and fluid transport in cultured alveolar epithelial type II cells (9, 10). To explain these apparently paradoxic results, it has been proposed that the up regulation of alveolar fluid clearance by TNF-α is secondary to the TIP domain TNF-α and not to the entire molecule. This hypothesis is supported by the fact that TIP upregulated alveolar fluid clearance by TNF-α receptor independent mechanisms in mice (11). Furthermore, subsequent experimental studies showed that the intratracheal administration of the synthetic peptide based on the TIP sequence reduced lung edema and improved lung function (12). Thus, the current experimental study in this issue of Critical Care Medicine (13) was designed to test the potential therapeutic value of TIP for treating pulmonary edema and to understand the mechanisms by which TIP reduced lung edema. The authors studied the effect of hydrostatic stress alone and found that elevation from 2 to 10 mm Hg in an isolated perfused rabbit lung preparation caused a change in lung vascular permeability, an effect that was attenuated by pretreatment with TIP. The investigators also studied the effect of endotoxin-induced permeability edema and again found that pretreatment with TIP reduced alveolar permeability. They also found that administration of a cAMP analog, dbcAMP, prevented edema formation by reducing permeability in both models. Interestingly, the cAMP analogue could not have worked by increasing alveolar fluid clearance because rabbits do not respond to cAMP stimulation with an increase in alveolar fluid clearance (1, 14). In a separate set of experiments, they found that TIP enhanced lung fluid clearance in isolated rabbit lungs, and that administration of either ouabain or amiloride, pharmacologic methods to inhibit Na, K,ATPase or epithelial sodium channel (ENaC), blocked the beneficial effects of TIP. Although prior investigators have shown that TIP works by up-regulating amiloride-sensitive transport, (11) these studies made the new observation that there was an increase in the number of sodium pump molecules transported to the basolateral cell surface of alveolar epithelial cells. Based on these results the authors propose that upregulating sodium apical and basolateral sodium transport probably explains the benefits of TIP. Since several studies from Sznajder’s research group have demonstrated that dopamine and beta-agonists can up-regulate alveolar fluid clearance by increasing Na,KATPase activity through translocation of the pumps to the basolateral surface, (15) and since the authors have clearly demonstrated that there is a translocation of the sodium pump in alveolar type II cells treated with TIP, this paradigm is reasonable. However, can we conclude, based on these results, that the effect of TIP is secondary to changes in alveolar liquid clearance? First the decreased edema observed in the hydrostatic model or the endotoxin model could be explained by a decrease in lung vascular permeability. Furthermore, the decrease in the volume of the epithelial lining fluid at the end of the experiment could be secondary to a decrease in the amount of lung edema produced in the presence of TIP. To clearly prove that the effect of TIP in these models is secondary to an increase in alveolar liquid clearance, it would be important to determine the effect of TIP on alveolar liquid clearance once the injury was well established. More experiments would also be necessary to better understand the effect of TIP on sodium transport in the lungs. Although the results clearly show that TIP can modulate sodium transport in the whole lung, more experiments are necessary to demonstrate the signaling pathways that are involved. Finally, it would be important to demonstrate that TIP can modulate transepithelial sodium transport since the results in these studies were obtained on cells that were subconfluent and probably not completely polarized. Would TIP influence sodium pump activity and transepithelial sodium transport in intact monolayers? What is the clinical significance of these findings? Several cAMP-independent and catecholamine-independent pathways have been identified that can up-regulate alveolar fluid clearance, including glucocorticoids, thyroid hormone, leukotriene D4, and keratinocyte growth factor (1, 2). In the current study, the authors found cAMP was as effective as TIP in preventing lung edema (Figs. 2 and 3). Thus, it is not clear that TIP would have an advantage compared to a cAMP agonist, although this conclusion needs to be tempered by awareness that responsiveness to cAMP agonists may be reduced if there were down-regulation of the beta-2 receptor in some pathologic conditions (1, 2). The only catecholamine-independent therapy that has been demonstrated to have an additive effect in terms of increasing alveolar fluid clearance is the combination of keratinocyte growth factor therapy with cAMP stimulation (16). Theoretically, two pharmacologic treatments that could have an additive effect in enhancing alveolar fluid clearance might have more clinical benefit in terms of enhancing the resolution of alveolar edema than one therapy along. In conclusion, continuing work on catecholamine-dependent and independent pathways to up-regulate alveolar fluid clearance and reduce microvascular lung permeability is important. It is equally important to understand the mechanisms by which potential new therapies can hasten the recovery of the injured alveolar epithelium in patients with acute lung injury. For any of the proposed therapies to up-regulate alveolar fluid clearance in patients with acute lung injury, there must be a sufficiently intact and responsive alveolar epithelium, (17) and ideally the treatment should be effective even if it is administered once the injury has already developed. TIP is an interesting molecule that may have therapeutic value to reduce the quantity of lung edema. More preclinical experiments are needed to understand the mechanisms involved in the protective effect of TIP under a variety of clinically relevant pathologic conditions.

A Framework and Mechanistically Focused, In Silico Method for Enabling Rational Translational Research

Abstract: A precondition for understanding if-and-when observations on wet-lab research models can translate to patients (and vice versa) is to have a method that enables anticipating how each system at the mechanism level will respond to the same or similar new intervention. A new class of mechanistic, in silico analogues is described. We argue that, although abstract, they enable developing that method. Building an analogue of each system within a common framework allows exploration of how one analogue might undergo (automated) metamorphosis to become the other. When successful, a concrete mapping is achieved. We hypothesize that such a mapping is, itself, an analogue of a corresponding mapping between the two referent systems. The analogue mapping can help establish how targeted aspects of the two referent systems are similar and different, at the mechanistic level and, importantly, at the systemic, emergent property level. The vision is that the analogues along with the metamorphosis method can be improved iteratively as part of a rational approach to translational research.

Protein C as a surrogate end-point for clinical trials of sepsis

Abstract: Identification of good surrogate end-points can greatly facilitate the design of clinical trials. Using data from PROWESS and ENHANCE, Shorr and colleagues explore the potential value of several plasma biomarkers for treatment trials of activated protein C for severe sepsis. Based on the framework proposed by Vasan, they tested the utility of several factors (protein C, interleukin-6, antithrombin III, prothrombin time, protein S, and d-dimers) as type 0, 1 and 2 biomarkers. Only protein C had acceptable performance characteristics as a type 2 biomarker, or surrogate end-point. The utility of protein C as a surrogate end-point for studies of severe sepsis must be validated in future prospective studies.