Showing papers by "Michael A. Matthay published in 2012"
TL;DR: Progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors, and on developing novel therapeutics that can facilitate and enhance lung repair.
Abstract: The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.
1,506 citations
TL;DR: The identified risk factors provide potential targets for reducing residual TRALI and little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody.
494 citations
TL;DR: Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia and enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups.
Abstract: Rationale Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied. Objective This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia. Methods and results Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli . 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p Conclusions Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs.
305 citations
TL;DR: Induction of intravenous bone marrow-derived human MSC increased survival from gram-negative peritoneal sepsis, in part by a monocyte-dependent increase in bacterial phagocytosis.
Abstract: The potential therapeutic value of cell-based therapy with mesenchymal stem cells (MSC) has been reported in mouse models of polymicrobial peritoneal sepsis. However, the mechanisms responsible for the beneficial effects of MSC have not been well defined. Therefore, we tested the therapeutic effect of intravenous bone marrow-derived human MSC in peritoneal sepsis induced by gram-negative bacteria. At 48 h, survival was significantly increased in mice treated with intravenous MSC compared with control mice treated with intravenous fibroblasts (3T3) or intravenous PBS. There were no significant differences in the levels of TNF-α, macrophage inflammatory protein 2, or IL-10 in the plasma. However, there was a marked reduction in the number of bacterial colony-forming units of Pseudomonas aeruginosa in the blood of MSC-treated mice compared with the 3T3 and PBS control groups. In addition, phagocytic activity was increased in blood monocytes isolated from mice treated with MSC compared with the 3T3 and PBS groups. Furthermore, levels of C5a anaphylotoxin were elevated in the blood of mice treated with MSC, a finding that was associated with upregulation of the phagocytosis receptor CD11b on monocytes. The phagocytic activity of neutrophils was not different among the groups. There was also an increase in alternately activated monocytes/macrophages (CD163- and CD206-positive) in the spleen of the MSC-treated mice compared with the two controls. Thus intravenous MSC increased survival from gram-negative peritoneal sepsis, in part by a monocyte-dependent increase in bacterial phagocytosis.
274 citations
TL;DR: Unlike von Willebrand factor, plasma angiopoietin-2 has differential prognostic value for mortality depending on the presence or absence of infection as an acute lung injury risk factor.
Abstract: Background:Angiopoietin-2 is a proinflammatory mediator of endothelial injury in animal models, and increased plasma angiopoietin-2 levels are associated with poor outcomes in patients with sepsis-associated acute lung injury. Whether angiopoietin-2 levels are modified by treatment strategies in pat
194 citations
TL;DR: How the effector mechanisms of platelets, mast cells, neutrophil extracellular traps, and the endothelium participate in combating local infections yet can induce organ injury during systemic infection is highlighted.
Abstract: Sepsis and septic shock lead to considerable morbidity and mortality in developed and developing countries. Despite advances in understanding the innate immune events that lead to septic shock, molecular therapies based on these advances have failed to improve sepsis mortality. The clinical failure of laboratory-derived therapies may be, in part, due to the pleiotropic consequences of the acute inflammatory response, which is the focus of this review. A brisk response to infecting organism is essential for pathogen containment and eradication. However, systemic spread of inflammation beyond a single focus leads to organ injury and higher mortality. The primary goal of this article is to discuss recent animal- and human-based scientific advances in understanding the host response to infection and to highlight how these defense mechanisms can be locally beneficial but systemically detrimental. There are other factors that determine the severity of sepsis that are beyond the scope of this review, including the virulence of the pathogen and regulation by Toll-like receptors. Specifically, this review focuses on how the effector mechanisms of platelets, mast cells, neutrophil extracellular traps (NETs), and the endothelium participate in combating local infections yet can induce organ injury during systemic infection.
111 citations
TL;DR: Current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment ofALI prior to the onset of respiratory failure that requires mechanical ventilation are discussed.
Abstract: Acute lung injury (ALI) remains a major cause of morbidity and mortality in critically ill patients. Despite improved understanding of the pathogenesis of ALI, supportive care with a lung protective strategy of mechanical ventilation remains the only treatment with a proven survival advantage. Most clinical trials in ALI have targeted mechanically ventilated patients. Past trials of pharmacologic agents may have failed to demonstrate efficacy in part due to the resultant delay in initiation of therapy until several days after the onset of lung injury. Improved early identification of at-risk patients provides new opportunities for risk factor modification to prevent the development of ALI and novel patient groups to target for early treatment of ALI before progression to the need for mechanical ventilation. This review will discuss current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment of ALI prior to the onset of respiratory failure that requires mechanical ventilation.
90 citations
TL;DR: This study supports the feasibility of future multi-center GWA investigations of ALi risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research.
Abstract: Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phase 1), we compared 600 European American trauma-associated ALI cases with 2266 European American population-based controls. We carried forward the top 1% of single nucleotide polymorphisms (SNPs) at p<0.01 to a replication phase (Phase 2) comprised of a nested case-control design sample of 212 trauma-associated ALI cases and 283 at-risk trauma non-ALI controls from ongoing cohort studies. SNPs that replicated at the 0.05 level in Phase 2 were subject to functional validation (Phase 3) using expression quantitative trait loci (eQTL) analyses in stimulated B-lymphoblastoid cell lines (B-LCL) in family trios. 159 SNPs from the discovery phase replicated in Phase 2, including loci with prior evidence for a role in ALI pathogenesis. Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (p = 0.0021). PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions. This study supports the feasibility of future multi-center GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research.
81 citations
TL;DR: Data suggest that β2AR agonists have broad anti‐inflammatory effects in the setting of ALI, while β2 AR agonists suppress JNK activation, the extent to which this can explain the blunted lung inflammatory responses in the ALI models remains to be determined.
Abstract: These studies were undertaken to extend emerging evidence that β(2) adrenergic receptor (β(2)AR) agonists, in addition to their bronchorelaxing effects, may have broad anti-inflammatory effects in the lung following onset of experimental acute lung injury (ALI). Young male C57BL/6 mice (25 g) developed ALI following airway deposition of bacterial LPS or IgG immune complexes in the absence or presence of appropriate stereoisomers (enantiomers) of β(2)AR agonists, albuterol or formoterol. Endpoints included albumin leak into lung and buildup of polymorphonuclear neutrophils and cytokines/chemokines in bronchoalveolar fluids. Both β(2)AR agonists suppressed lung inflammatory parameters (IC(50)=10(-7) M). Similar effects of β(2)AR agonists on mediator release were found when mouse macrophages were stimulated in vitro with LPS. The protective effects were associated with reduced activation (phosphorylation) of JNK but not of other signaling proteins. Collectively, these data suggest that β(2)AR agonists have broad anti-inflammatory effects in the setting of ALI. While β(2)AR agonists suppress JNK activation, the extent to which this can explain the blunted lung inflammatory responses in the ALI models remains to be determined.
80 citations
TL;DR: Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.
Abstract: Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severit...
71 citations
TL;DR: Rats with the metabolic syndrome have ineffective inflammation-resolving mechanisms that represent plausible reasons for the exaggerated and persistent PCD.
Abstract: The cholinergic antiinflammatory pathway (CAP), which terminates in the spleen, attenuates postoperative cognitive decline (PCD) in rodents. Surgical patients with metabolic syndrome exhibit exaggerated and persistent PCD that is reproduced in postoperative rats selectively bred for easy fatigability and that contain all features of metabolic syndrome (low-capacity runners [LCRs]). We compared the CAP and lipoxin A(4) (LXA(4)), another inflammation-resolving pathway in LCR, with its counterpart high-capacity runner (HCR) rats. Isoflurane-anesthetized LCR and HCR rats either underwent aseptic trauma involving tibial fracture (surgery) or not (sham). At postoperative d 3 (POD3), compared with HCR, LCR rats exhibited significantly exaggerated PCD (trace fear conditioning freezing time 43% versus 57%). Separate cohorts were killed at POD3 to collect plasma for LXA4 and to isolate splenic mononuclear cells (MNCs) to analyze CAP signaling, regulatory T cells (Tregs) and M2 macrophages (M2 Mφ). Under lipopolysaccharide (LPS) stimulation, tumor necrosis factor (TNF)-α produced by splenic MNCs was 117% higher in LCR sham and 52% higher in LCR surgery compared with HCR sham and surgery rats; LPS-stimulated TNF-α production could not be inhibited by an α7 nicotinic acetylcholine receptor agonist, whereas inhibition by the β(2) adrenergic agonist, salmeterol, was significantly less (-35%) than that obtained in HCR rats. Compared to HCR, sham and surgery LCR rats had reduced β(2) adrenergic receptor-expressing T lymphocytes (59%, 44%), Tregs (47%, 54%) and M2 Mφ (45%, 39%); surgical LCR rats' hippocampal M2 Mφ was 66% reduced, and plasma LXA4 was decreased by 120%. Rats with the metabolic syndrome have ineffective inflammation-resolving mechanisms that represent plausible reasons for the exaggerated and persistent PCD.
TL;DR: PKC-α and arginase I are identified as potential upstream and downstream therapeutic targets in PLY-induced pulmonary endothelial dysfunction and a specific PKC-α inhibitor and the TNF-derived tonoplast intrinsic protein peptide are able to prevent activation of arginases in HL-MVECs and to reduce PLY's endothelial hyperpermeability in mice.
Abstract: Antibiotics-induced release of the pore-forming virulence factor pneumolysin (PLY) in patients with pneumococcal pneumonia results in its presence days after lungs are sterile and is a major factor responsible for the induction of permeability edema. Here we sought to identify major mechanisms mediating PLY-induced endothelial dysfunction. We evaluated PLY-induced endothelial hyperpermeability in human lung microvascular endothelial cells (HL-MVECs) and human lung pulmonary artery endothelial cells in vitro and in mice instilled intratracheally with PLY. PLY increases permeability in endothelial monolayers by reducing stable and dynamic microtubule content and modulating VE-cadherin expression. These events, dependent upon an increased calcium influx, are preceded by protein kinase C (PKC)-α activation, perturbation of the RhoA/Rac1 balance, and an increase in myosin light chain phosphorylation. At later time points, PLY treatment increases the expression and activity of arginase in HL-MVECs. Arginase inhibition abrogates and suppresses PLY-induced endothelial barrier dysfunction by restoring NO generation. Consequently, a specific PKC-α inhibitor and the TNF-derived tonoplast intrinsic protein peptide, which blunts PLY-induced PKC-α activation, are able to prevent activation of arginase in HL-MVECs and to reduce PLY-induced endothelial hyperpermeability in mice. Arginase I (AI)+/−/arginase II (AII)−/− C57BL/6 mice, displaying a significantly reduced arginase I expression in the lungs, are significantly less sensitive to PLY-induced capillary leak than their wild-type or AI+/+/AII−/− counterparts, indicating an important role for arginase I in PLY-induced endothelial hyperpermeability. These results identify PKC-α and arginase I as potential upstream and downstream therapeutic targets in PLY-induced pulmonary endothelial dysfunction.
TL;DR: It is concluded that the chorion of human term placenta is an abundant source of multipotent stem cells that are promising candidates for cell‐based therapies.
Abstract: We describe human chorionic mesenchymal stem cell (hCMSC) lines obtained from the chorion of human term placenta with high therapeutic potential in human organ pathology. hCMSCs propagated for more than 100 doublings without a decrease in telomere length and with no telomerase activity. Cells were highly positive for the embryonic stem cell markers OCT-4, NANOG, SSEA-3, and TRA-1-60. In vitro, cells could be differentiated into neuron-like cells (ectoderm), adipocytes, osteoblasts, endothelial-like cells (mesoderm), and hepatocytes (endoderm)-derivatives of all three germ layers. hCMSCs effectively facilitated repair of injured epithelium as demonstrated in an ex vivo-perfused human lung preparation injured by Escherichia coli endotoxin and in in vitro human lung epithelial cultures. We conclude that the chorion of human term placenta is an abundant source of multipotent stem cells that are promising candidates for cell-based therapies.
TL;DR: Evidence is provided that the functional rs2814778 polymorphism in the gene encoding DARC is associated with worse clinical outcomes among African Americans with ALI, possibly via an increase in circulating IL-8.
TL;DR: JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin.
Abstract: Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na+ transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na+/K+-ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na+ uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.
TL;DR: Histopathology 61, 98–106 shows clear trends in prognosis for central giant cell granuloma in meningitis, and these trends are likely to improve with age and disease progression.
Abstract: Aims
The relationship of mast cells to the pathogenesis of lung fibrosis remains undefined despite recognition of their presence in the lungs of patients with pulmonary fibrosis. This study was performed to characterize the relationship of mast cells to fibrotic lung diseases.
TL;DR: Findings show that GW328267C has beneficial effects in experimental models of ALI and may be a useful agent for treating patients with ALI or prophylactically to prevent ALI.
Abstract: There is a significant unmet need for treatments of patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). The primary mechanism that leads to resolution of alveol...
TL;DR: These experiments indicate that IQGAP1 is necessary for S1P-mediated vascular barrier protection during acute lung injury and is required for junctional localization of the barrier-protective integrin α(v)β(3).
Abstract: We recently reported that integrin αvβ3 is necessary for vascular barrier protection in mouse models of acute lung injury and peritonitis. Here, we used mass spectrometric sequencing of integrin co...
TL;DR: It is suggested that vasopressor use may be a marker of alveolar-capillary barrier permeability in ALI and provide justification for new therapies that enhanceAlveolar epithelial and endothelial barrier integrity in ALi, particularly in patients with shock.
Abstract: The rate of alveolar fluid clearance (AFC) is associated with mortality in clinical acute lung injury (ALI). Patients with ALI often develop circulatory shock, but how shock affects the rate of AFC is unknown. To determine the effect of circulatory shock on the rate of AFC in patients with ALI, the rate of net AFC was measured in 116 patients with ALI by serial sampling of pulmonary edema fluid. The primary outcome was the rate of AFC in patients with shock compared with those without shock. We also tested the effects of shock severity and bacteremia. Patients with ALI and shock (n = 86) had significantly slower rates of net AFC compared with those without shock (n = 30, P = 0.03), and AFC decreased significantly as the number of vasopressors increased. Patients with positive blood cultures (n = 21) had slower AFC compared with patients with negative blood cultures (n = 96, P = 0.023). In addition, the edema fluid-to-plasma protein ratio, an index of alveolar-capillary barrier permeability, was highest in patients requiring the most vasopressors (P < 0.05). Patients with ALI complicated by circulatory shock and bacteremia had slower rates of AFC compared with patients without shock or bacteremia. An impaired capacity to reabsorb alveolar edema fluid may contribute to high mortality among patients with sepsis-induced ALI. These findings also suggest that vasopressor use may be a marker of alveolar-capillary barrier permeability in ALI and provide justification for new therapies that enhance alveolar epithelial and endothelial barrier integrity in ALI, particularly in patients with shock.
TL;DR: Comparison of chest radiograph scoring to lung weight as a quantitative index of pulmonary edema in organ donors and the California Transplant Donor Network shows clear trends in survival and morbidity.
Abstract: Quantification of the degree of pulmonary edema in organ donors is useful for assessing the clinical severity of pulmonary edema, determining response to therapy, and as an endpoint for therapeutic trials. Currently, there is no accurate non-invasive method for assessing the degree of pulmonary edema. We tested the performance of a four-quadrant chest radiographic scoring system compared to quantification of pulmonary edema by excised lung weight in 84 donors whose lungs were not used for transplantation. Chest radiographs were taken 3.6 ± 3.0 h prior to organ procurement and were scored by two of the authors. Lungs were excised without perfusion and individually weighed. The chest radiographic scoring system had good performance: correlation between total radiographic score and total lung weight of 0.61, p 1000 g) was 0.80. This chest radiographic scoring system may potentially be used to assess the clinical severity of pulmonary edema and may be useful as part of the evaluation of donors for suitability for lung transplantation.
TL;DR: A mouse model of ALI is reported that reproduces several features of the pathophysiology of ALi, including the effects of age, chronic medical diseases such as liver and renal insufficiency, and the impact of genetic and environmental factors.
Abstract: Animal models of acute lung injury (ALI) have contributed significantly to our understanding of the pathogenesis and pathophysiology of the clinical syndrome of ALI and acute respiratory distress syndrome (ARDS) [1]. Investigators have used a wide variety of small- and large-animal models in order to understand the mechanisms of injury to both the lung endothelial and epithelial barriers, as well as to test novel therapeutic strategies [2–4]. All animal models are limited in their ability to model the complex clinical syndrome of ALI/ARDS because they cannot replicate several of the confounding factors, including the effects of age, chronic medical diseases such as liver and renal insufficiency, and the impact of genetic and environmental factors that may contribute to the clinical syndrome of ALI/ARDS [3]. Nevertheless, animal models have made important contributions to understanding several of the mechanisms responsible for the development of lung injury [4, 5].
In this issue of the European Respiratory Journal , Patel et al. [6] report a mouse model of ALI that reproduces several features of the pathophysiology of ALI. …
TL;DR: In this paper, mesenchymal stem/stromal cells (MSCs) were found to reduce collagen deposition in the bleomycin model of pulmonary fibrosis and reduce lung injury and improve survival following intrapulmonary delivery of endotoxin or Escherichia coli.
Abstract: BONE MARROW-DERIVED mesenchymal stem/stromal cells (MSCs) are self-renewing multipotent cells with therapeutic effects in diverse models of tissue injury (27). In the rodent lung, MSCs reduce collagen deposition in the bleomycin model of pulmonary fibrosis (26) and reduce lung injury and improve survival following intrapulmonary delivery of endotoxin or Escherichia coli (10, 11) and following severe gram-negative peritonitis (18). In the hyperoxia model of bronchopulmonary dysplasia, exposure to high concentrations of oxygen during early postnatal life in rats and mice causes simplification of alveolar and lung capillary structure and reduced pulmonary capillary surface area, leading to pulmonary hypertension. Two groups reported simultaneously in 2009 that MSCs given by airway to rats (12) or by blood to mice (2) during prolonged hyperoxia in early postnatal life prevented arrested alveolar growth. However, engraftment of MSCs during hyperoxia and in other models has not accounted for the therapeutic effects, thus prompting a search for other mechanisms. MSCs are potent immunomodulators, suppressing several functions of lymphocytes, natural killer cells, and monocytes (1), and reduce inflammatory cell lung infiltrates and cytokines during sepsis and acute lung injury (11, 23, 25). In addition, MSCs have direct antibacterial effects (19), secrete epithelial growth factors (21), and can rescue epithelial cellular bioenergetics with mitochondrial transfer (14). MSCs and the Stem Cell Niche
TL;DR: Data suggest that chronic increases in PBF lead to both functional and structural aberrations of lung lymphatics, which have important therapeutic implications that warrant further study.
Abstract: Abnormalities of the lymphatic circulation are well recognized in patients with congenital heart defects. However, it is not known how the associated abnormal blood flow patterns, such as increased pulmonary blood flow (PBF), might affect pulmonary lymphatic function and structure. Using well-established ovine models of acute and chronic increases in PBF, we cannulated the efferent lymphatic duct of the caudal mediastinal node and collected and analyzed lymph effluent from the lungs of lambs with acutely increased PBF (n = 6), chronically increased PBF (n = 6), and age-matched normal lambs (n = 8). When normalized to PBF, we found that lymph flow was unchanged following acute increases in PBF but decreased following chronic increases in PBF. The lymph:plasma protein ratio decreased with both acute and chronic increases in PBF. Lymph bioavailable nitric oxide increased following acute increases in PBF but decreased following chronic increases in PBF. In addition, we found perturbations in the transit kinetics of contrast material through the pleural lymphatics of lambs with chronic increases in PBF. Finally, there were structural changes in the pulmonary lymphatic system in lambs with chronic increases in PBF: lymphatics from these lambs were larger and more dilated, and there were alterations in the expression of vascular endothelial growth factor-C, lymphatic vessel endothelial hyaluronan receptor-1, and Angiopoietin-2, proteins known to be important for lymphatic growth, development, and remodeling. Taken together these data suggest that chronic increases in PBF lead to both functional and structural aberrations of lung lymphatics. These findings have important therapeutic implications that warrant further study.
TL;DR: The findings indicate for the first time that the function of uPA in patients with ALI/ARDS may be modulated by α(2)-M and that the effects may include the regulation of the fibrinolytic and signaling activities of u PA.
Abstract: The level of active urokinase (uPA) is decreased in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) whereas α(2)-macroglobulin (α(2)-M), a plasma proteinase inhibitor, is a major component of these fluids. Since there have been reports describing the ability of α(2)-M to form complexes with uPA in vitro, we hypothesized that α(2)-M may interact with uPA in the lung to modulate its biological activity. Pulmonary edema fluids and lung tissues from patients with ALI/ARDS were evaluated for the presence of uPA associated with α(2)-M. Complexes between α(2)-M and uPA were detected in alveolar edema fluids as well as in lungs of patients with ALI/ARDS where they were located mainly in close proximity to epithelial cells. While uPA bound to α(2)-M retains its amidolytic activity towards low-molecular-weight substrates, it is not inhibited by its main physiological inhibitor, plasminogen activator inhibitor 1. We also investigated the functional consequences of formation of complexes between uPA and α(2)-M in vitro. We found that when α(2)-M:uPA complexes were added to cultures of human bronchial epithelial cells (BEAS-2B), activation of nuclear factor-κB as well as production of interleukin-6 and -8 was substantially suppressed compared with the addition of uPA alone. Our findings indicate for the first time that the function of uPA in patients with ALI/ARDS may be modulated by α(2)-M and that the effects may include the regulation of the fibrinolytic and signaling activities of uPA.
TL;DR: In their study, Cao et al. found that intravenous infusion of EPC 4 h after the induction of endotoxin-induced injury significantly improved oxygenation and histologic indices of lung injury, including the infiltration of polymorphonuclear cells, the extent of hyaline membrane formation and hemorrhage, and the lung wet-todry ratio as a measure of pulmonary edema at 48 h.
Abstract: A CUTE lung injury (ALI) and acute respiratory distress syndrome remain one of the most common causes of acute respiratory failure in critically ill patients. Despite extensive research, current treatment options remain primarily supportive with lung protective ventilation and a fluid conservative strategy. Recently, the potential use of cell-based therapy has generated considerable interest for the treatment of lung diseases, including ALI. In this month’s issue of ANESTHESIOLOGY, Cao et al. add to the literature by studying the potential therapeutic role of circulating autologous endothelial progenitor cells (EPC) in endotoxin-induced ALI in rabbits. Much of the initial interest in cell-based therapy for treatment of ALI originated from the multipotent nature of bone-marrow–derived cells. In 2001, Krause et al. reported that a single bone-marrow–derived hematopoietic stem cell in mice could give rise to cells of multiple different organs, including the lung. The authors reported up to 20% engraftment of bone-marrow–derived cells in the lung, including epithelial cells, from a single hematopoietic precursor. This report stimulated additional investigations into the possibility that adult bone-marrow–derived stem cells might be able to regenerate the lung epithelium and/or endothelium. Initially, the regenerative potential of bone-marrow– derived EPC was studied predominantly in models of endothelial injury from cardiovascular disease, particularly after myocardial infarction or pulmonary arterial hypertension. More recently, several investigators demonstrated an improvement in pulmonary alveolar-capillary barrier function in lung injury models, including oleic acid in rabbits and endotoxin in rats after EPC therapy. However, subsequent studies indicate that the level of engraftment of bone-marrow–derived cells in lung injury was low, with observed rates of less than 5%. In their study, Cao et al. found that intravenous infusion of EPC 4 h after the induction of endotoxin-induced injury significantly improved oxygenation (ratio of partial pressure of oxygen to fraction of inspired oxygen ratio) and histologic indices of lung injury, including the infiltration of polymorphonuclear cells, the extent of hyaline membrane formation and hemorrhage, and the lung wet-todry ratio as a measure of pulmonary edema at 48 h. EPC infusion suppressed the concentrations of the inflammatory cytokine, IL-1 , and an adhesion molecule, ICAM-1, and also reduced concentrations of reactive oxygen species, nitric oxide and malondialdehyde. The authors speculated that the therapeutic effect of EPC could be attributable to endothelial repair of the damaged pulmonary vascular wall by intercalating of the EPC into the injured capillaries or immunomodulation of the inflammatory and oxidant responses, including release of the antiinflammatory cytokine IL-10 and induction of higher concentrations of superoxide dismutase. The authors studied the trafficking of the EPC to the lung with immunohistochemistry and fluorescence-conjugated cell tracers for 48 h. However, because of the short time period of injury studied and the fact that the intravenous infusion of bone-marrow– derived cells typically are initially trapped in the pulmonary microcirculation, additional studies are needed to determine the contribution of engraftment in the therapeutic response of EPC. Cao et al. also identified the immunomodulatory properties of EPC as another potential therapeutic mechanism underlying the beneficial effect of EPC in lung injury. The article by Cao et al. has several limitations. First, the authors were not able to identify the mechanisms of benefit Photomicrograph: Courtesy of Brian Wainger, M.D., Ph.D.
TL;DR: No significant associations were found between βAR SNPs and cardiac dysfunction in 364 donors managed from 2007–2008, perhaps due to changes in donor management, lack of power in this validation cohort, or the absence of a true association.
TL;DR: The use of controlled DCD lungs is associated with similar clinical outcomes as LTx using BDD donors, and led to decreased incidence of severe PGD in the DCD population.
Abstract: Purpose: To review our experience after 5 years of lung transplantation (LTx) using lung donation after cardiac death (DCD). Methods and Materials: Outcomes DCD LTx were compared with contemporaneous recipients receiving lungs from brain death donors(BDD). Incidence of severe primary graft dysfunction(PGD), ICU and hospital length of stay(LOS), 30 day mortality, and overall survival were analyzed. Results: During the study period, 448 LTx were performed; 408 from BDD and 40 from DCD donors. The proportion of DCD donors among cadaveric donors and the proportion lung transplants using DCD donors are shown in Figure 1. Recipient diagnosis was similar in both groups (BDD vs. DCD): Emphysema (26% vs. 30%), pulmonary fibrosis (33% vs. 32%), cystic fibrosis (20% vs. 23%), and others (22% vs. 14%). Median donor P/F was 422 mmHg in BDD group and 360 mmHg in DCD group (p 0.004). Median recipient P/F at ICU arrival was 350 mmHg in BDD vs. 301 mmHg in DCD (p 0.06). Incidence of severe primary graft dysfunction after LTx requiring ECMO support was 2.7% in BDD and 7.5% in DCD (p 0.14). Median ICU stay was 4 days in BDD and 5 days in DCD. Median hospital LOS was 23 days in both groups (p 0.05). 30 day, 1 year and 3 year proportional survival were 95.7%, 84%, and 70% in BDD and 95%, 85%, and 64% in DCD respectively (P 0.05 for all comparisons). Within the DCD group, 18 lungs underwent ex vivo lung perfusion (EVLP). Lungs undergoing EVLP had decreased incidence of PGD 3 at 72h after LTx: 0 vs 22% (p 0.04). Conclusions: Lung transplantation using DCD donors currently accounts for 15-20% of our LTx activities. The use of controlled DCD lungs is associated with similar clinical outcomes as LTx using BDD donors. EVLP led to decreased incidence of severe PGD in the DCD population.
20 Dec 2012
TL;DR: This presentation provided a brief historical perspective from the 1998 Aspen Conference on Acute Lung Injury, highlighting the discussion of clinical definitions, and 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.
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 cli...
20 Dec 2012
TL;DR: Observations suggest that avb3 and avb5 differentially regulate the pulmonary endothelial permeability response to edemagenic agonists through distinct effects on the actin cytoskeleton.
Abstract: Integrins avb3 and avb5 Reciprocally Regulate Pulmonary Endothelial Barrier Function through Differential Effects on the Actin Cytoskeleton George Su1,2, Nanyan Wu1, Amha Atakilit1, Jiyeun Kate Kim1, and Dean Sheppard1,2 Lung Biology Center, Division of Pulmonary and Critical Care Medicine, University of California at San Francisco, San Francisco, California We have shown the integrin avb5 to be a central regulator of lung vascular permeability and pulmonary endothelial barrier function—both considered pathologic hallmarks of acute lung injury (ALI). avb5 co-localizes with the closely related integrin, avb3, at focal adhesions in pulmonary endothelial cells, and both integrins recognize overlapping ligands. Despite these similarities, inhibition of avb3 and avb5 have strikingly different effects on agonist-induced pulmonary endothelial permeability: inhibition of avb3 dramatically enhances increased permeability, whereas inhibition of avb5 prevents increased permeability. These integrins also have dramatically different effects on reorganization of the actin cytoskeleton in these cells. Blockade of avb5 inhibits agonist-induced formation of actin stress fibers, whereas blockade of avb3 specifically inhibits increases in cortical actin organization induced by sphingosine-1 phosphate and constitutively active Rac1. These observations suggest that avb3 and avb5 differentially regulate the pulmonary endothelial permeability response to edemagenic agonists through distinct effects on the actin cytoskeleton. Optimal therapies targeting integrin avb5 for the treatment and/or prevention of ALI may thus be critically dependent on the development of selective antagonists that do not target the closely related integrin avb3. Conflict of Interest Statement: G.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.A. is a co-owner (with D.S.) of a filed patent (pending) covering blockade of integrin avb5 for the treatment of acute lung injury. J.K.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.S. and A.A. are co-owners of a filed patent (pending) covering blockade of integrin avb5 for the treatment of acute lung injury. He has had a sponsored research agreement with Biogen Idec to cover work on anti-integrin antibodies and acute lung injury for $150,000/year (total costs) since January 2002. UCSF co-owns all intellectual property of UCSF faculty, including the pending patent described above. The institution also collects indirect costs on the sponsored research agreement with Biogen Idec, described above. (Received in original form November 13, 2007; accepted in final form November 16, 2007) Funded by NHLBI HL083950 (D.S.) and 1K08HL083097-01A1 (G.S.). Correspondence and requests for reprints should be addressed to George Su, M.D., 1550 4th Street, Room 545, San Francisco, CA 94158. E-mail: george.