Nikolaos Maniatis | University of Pittsburgh (original) (raw)

Papers by Nikolaos Maniatis

Anaesthesia and intensive care

The aim of the study was to calculate the in vitro inspiratory resistance (R(ETT)) of adult endot... more The aim of the study was to calculate the in vitro inspiratory resistance (R(ETT)) of adult endotracheal tubes (ETT), via the end-inspiratory occlusion method, and to apply this method in vivo in order to estimate R(ETT) value in real time. By plotting R(ETT) over inspiratory flow (V) and calculating Rohrer's coefficients of linear and nonlinear resistance, K1 and K2 respectively, we determined the resistive behaviour of each ETT. Peak and plateau pressures were recorded at both proximal and distal sites of the ETT after applying a three-second occlusion under constant flow. Distal pressure was obtained via an intraluminal catheter R(ETT) was calculated as (P(peak) - P(plateau))/(V), at both sites. R(ETT) value resulted from the difference R(proximal) - R(distal). Graph R(ETT) over (V) was plotted and Rohrer's constants were calculated by the method of least squares. For ETTs with inner diameter 9.0, 8.5, 8.0, 7.5, 7.0 and 6.5 mm, K2 was 2.42, 3.05, 4.65, 6.01, 9.17 and 12.8...

B110. GENOMICS, METABOLOMICS, AND EPIGENETICS IN LUNG DISEASE: LATE BREAKING ABSTRACTS, 2012

Critical Care, 2010

We compliment Dr Müller and colleagues [1] for their experiment on the protective role of simvast... more We compliment Dr Müller and colleagues [1] for their experiment on the protective role of simvastatin against ventilator-induced lung injury (VILI). Th eir results are in line with those of a relevant study published recently by our research team; we also showed that pretreatment with statins (specifi cally atorvastatin) attenuates VILI [2]. By synthesizing the fi ndings of the above contributions [1,2], one could make several points.

Intensive Care Medicine, 2008

ABSTRACT Sepsis is a serious disorder with high morbidity and mortality worldwide and an increasi... more ABSTRACT Sepsis is a serious disorder with high morbidity and mortality worldwide and an increasing incidence [1]. Sepsis is the result of an overwhelming and maladaptive response of the host organism to the invasion of pathogenic microorganisms, which generates an uncontrolled and auto-destructive inflammatory process [2]. The septic syndrome carries various degrees of severity, and critically ill patients often develop sepsis-induced acute organ dysfunction (i.e., severe sepsis) and fluid-refractory hypotension (i.e., septic shock). Extensive research performed during the past two decades has greatly improved our understanding of the mechanisms underlying sepsis pathophysiology: Widespread devastating inflammation and microvascular coagulation are common denominators in severe sepsis, while endothelial cell dysfunction appears to be a key determinant in the development of the syndrome [3, 4].

Minerva anestesiologica, 2015

The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant... more The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant and anti-inflammatory pathways. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in the septic process is under investigation. In this study, we assessed the role of sEPCR levels as an early indicator of sepsis development. Plasma sEPCR levels were measured in 59 critically-ill non-septic patients at the time of admission to the intensive care unit (ICU). Multiple logistic regression analysis was performed to identify potential risk factors for sepsis development and Cox-Regression models were fitted for variables to examine their relationship with time to sepsis development. Thirty patients subsequently developed sepsis and 29 did not. At ICU admission, sequential organ failure assessment (SOFA) scores were significantly higher in the subsequent sepsis group as compared to the non sep...

Current opinion in critical care, 2008

Since pulmonary edema from increased endothelial permeability is the hallmark of acute lung injur... more Since pulmonary edema from increased endothelial permeability is the hallmark of acute lung injury, a frequently encountered entity in critical care medicine, the study of endothelial responses in this setting is crucial to the development of effective endothelial-targeted treatments. From the enormous amount of research in the field of endothelial pathophysiology, we have focused on work delineating endothelial alterations elicited by noxious stimuli implicated in acute lung injury. The bulk of the material covered deals with molecular and cellular aspects of the pathogenesis, reflecting current trends in the published literature. We initially discuss pathways of endothelial dysfunction in acute lung injury and then cover the mechanisms of endothelial protection. Several experimental treatments in animal models are presented, which aid in the understanding of the disease pathogenesis and provide evidence for potentially useful therapies. Mechanistic studies have delivered several i...

A66. PRECLINICAL MODELS OF ACUTE LUNG INJURY, 2010

Pulmonary Circulation, 2012

Caveolin-1 is a key regulator of pulmonary endothelial barrier function. Here, we tested the hypo... more Caveolin-1 is a key regulator of pulmonary endothelial barrier function. Here, we tested the hypothesis that caveolin-1 expression is required for ventilator-induced lung injury (VILI). Caveolin-1 gene-disrupted (Cav-1 -/-) and age, sex, and strain-matched wild-type (WT) control mice were ventilated using two protocols: volume-controlled with protective (8 mL/kg) versus injurious (21 mL/Kg) tidal volume for up to 6 hours; and pressure-controlled with protective (airway pressure = 12 cm H 2 O) versus injurious (30 cm H 2 O) ventilation to induce lung injury. Lung microvascular permeability (whole-lung 125 I-albumin accumulation, lung capillary filtration coefficient [K f, c ]) and inflam matory markers (bronchoalveolar lavage [BAL] cytokine levels and neutrophil counts) were measured. We also evaluated histologic sections from lungs, and the time course of Src kinase activation and caveolin-1 phosphorylation. VILI induced a 1.7-fold increase in lung 125 I-albumin accumulation, fourfold increase in K f, c , significantly increased levels of cytokines CXCL1 and interleukin-6, and promoted BAL neutrophilia in WT mice. Lung injury by these criteria was significantly reduced in Cav-1 -/mice but fully restored by i.v. injection of liposome/Cav-1 cDNA complexes that rescued expression of Cav-1 in lung microvessels. As thrombin is known to play a significant role in mediating stretch-induced vascular injury, we observed in cultured mouse lung microvascular endothelial cells (MLECs) thrombin-induced increase in albumin hyperpermeability and phosphorylation of p44/42 MAP kinase in WT but not in Cav-1 -/-MLECs. Thus, caveolin-1 expression is required for mechanical stretch-induced lung inflammation and endothelial hyperpermeability in vitro and in vivo.

Advances in Experimental Medicine and Biology, 2012

The primary function of the mammalian lung is to facilitate diffusion of oxygen to venous blood a... more The primary function of the mammalian lung is to facilitate diffusion of oxygen to venous blood and to ventilate carbon dioxide produced by catabolic reactions within cells. However, it is also responsible for a variety of other important functions, including host defense and production of vasoactive agents to regulate not only systemic blood pressure, but also water, electrolyte and acid-base balance. Caveolin-1 is highly expressed in the majority of cell types in the lung, including epithelial, endothelial, smooth muscle, connective tissue cells, and alveolar macrophages. Deletion of caveolin-1 in these cells results in major functional aberrations, suggesting that caveolin-1 may be crucial to lung homeostasis and development. Furthermore, generation of mutant mice that under-express caveolin-1 results in severe functional distortion with phenotypes covering practically the entire spectrum of known lung diseases, including pulmonary hypertension, fibrosis, increased endothelial permeability, and immune defects. In this Chapter, we outline the current state of knowledge regarding caveolin-1-dependent regulation of pulmonary cell functions and discuss recent research findings on the role of caveolin-1 in various pulmonary disease states, including obstructive and fibrotic pulmonary vascular and inflammatory diseases.

Cytokine, 2014

Widespread endothelial activation and dysfunction often precede clinical sepsis. Several endothel... more Widespread endothelial activation and dysfunction often precede clinical sepsis. Several endotheliumrelated molecules have been investigated as potential biomarkers for early diagnosis and/or prognosis of sepsis, providing different results depending on study designs. Such factors include endothelial adhesion molecules like E-and P-selectin, and the intercellular adhesion molecule-1, vascular endothelial cadherin, growth factors such as Angiopoietin-1 and -2 and vascular endothelial growth factor, as well as von Willebrand factor antigen. We sought to investigate whether circulating biomarkers of endothelial activation/dysfunction measured at ICU admission are associated with subsequent sepsis development.

Vascular pharmacology, 2008

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS... more Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.

Shock, 2012

Aspiration of hydrochloric acid (HCl)-containing gastric juice leads to acute lung injury (ALI) a... more Aspiration of hydrochloric acid (HCl)-containing gastric juice leads to acute lung injury (ALI) and hypoxemic respiratory failure due to an exuberant inflammatory response associated with pulmonary edema from increased vascular and epithelial permeability. The aim of this study was to determine the role and signaling mechanisms of tumor necrosis factor α (TNF-α) in experimental ALI from HCl aspiration using a combination of genetic animal models and pharmacologic inhibition strategies. To this end, HCl was instilled intratracheally to mice, followed by respiratory system elastance measurement, bronchoalveolar lavage, and lung tissue harvesting 24 h after injection. Hydrochloric acid instillation induced an inflammatory response in the lungs of wild-type mice, evidenced as increased bronchoalveolar lavage total cells, neutrophils, and total protein; histologic lung injury score; and respiratory system elastance, whereas TNF-α receptor I mRNA levels were maintained. These alterations could be prevented by pretreatment with etanercept or genetic deletion of the 55-kd TNF-α receptor I, but not by deletion of the TNF-α gene. Hydrochloric acid induced a 6-fold increase in apoptotic, caspase 3-positive cells in lung sections from wild-type mice, which was abrogated in mice lacking TNF-α receptor I. In immunoblotting and immunohistochemistry studies, HCl stimulated signaling via p44/42 and c-Jun N-terminal kinase, which was blocked in TNF-α receptor I knockout mice. In conclusion, ALI induced by HCl requires TNF-α receptor I function and associates with activation of downstream proinflammatory signaling pathways p44/42 and c-Jun N-terminal kinase.

Shock, 2011

Microdialysis (MD) provides the opportunity to monitor tissue metabolic changes. This study aimed... more Microdialysis (MD) provides the opportunity to monitor tissue metabolic changes. This study aimed to describe the kinetics of MD-derived metabolites during the course of critical sepsis, to assess whether these metabolites are useful in grading sepsis severity, and to investigate their prognostic use. To this end, 54 mechanically ventilated septic patients were prospectively studied, out of which 39 had shock. Upon sepsis onset, an MD catheter was inserted into the subcutaneous adipose tissue of the upper thigh. Dialysate samples were analyzed for glucose, pyruvate, lactate, and glycerol. Sampling was performed six times per day for a maximum of 6 days. The daily mean values of MD measurements were calculated for each patient. Arterial blood was analyzed for glucose, lactate, and glycerol concomitantly with dialysate sampling. Blood glucose and tissue glucose levels along with lactate levels were high during the entire study period. Tissue pyruvate and glycerol were also raised, whereas the lactate-pyruvate ratio was preserved. At study entry, patients with septic shock had higher tissue lactate (3.3 vs. 1.9 mmol/L, P = 0.01) and glycerol (340 vs. 169 2mol/L, P = 0.04) levels compared with those without shock. Nonsurvivors had higher tissue lactate (P = 0.008), glycerol (P = 0.004), and pyruvate (P = 0.002) levels than survivors during the whole observation period. Logistic regression analysis showed that age (odds ratio [OR], 1.075; 95% confidence interval [CI], 1.004Y1.150; P = 0.03), Sequential Organ Failure Assessment score on day 1 (OR, 1.550; 95% CI, 1.043Y2.312; P = 0.03), and tissue glycerol on day 1 (OR, 1.007; 95% CI, 1.001Y1.012; P = 0.01) predicted mortality independently. In conclusion, critical sepsis is characterized by high tissue lactate and pyruvate levels and a preserved lactate-pyruvate ratio, suggesting a nonischemic mechanism for raised blood lactate levels. Septic shock is associated with higher tissue lactate and glycerol levels compared with sepsis without shock. Elevated tissue lactate, pyruvate, and glycerol levels are related to poor clinical outcome, with the latter constituting an independent predictor.

Oncogene, 2013

Secreted phosphoprotein-1 (SPP1) promotes cancer cell survival and regulates tumor-associated ang... more Secreted phosphoprotein-1 (SPP1) promotes cancer cell survival and regulates tumor-associated angiogenesis and inflammation, both central to the pathogenesis of malignant pleural effusion (MPE). Here, we examined the impact of tumor-and host-derived SPP1 in MPE formation and explored the mechanisms by which the cytokine exerts its effects. We used a syngeneic murine model of lung adenocarcinoma-induced MPE. To dissect the effects of tumor-versus host-derived SPP1, we intrapleurally injected wild-type and SPP1-knockout C57/BL/6 mice with either wild-type or SPP1-deficient syngeneic lung cancer cells. We demonstrated that both tumor-and host-derived SPP1 promoted pleural fluid accumulation and tumor dissemination in a synergistic manner (Po0.001). SPP1 of host origin elicited macrophage recruitment into the cancer-affected pleural cavity and boosted tumor angiogenesis, whereas tumor-derived SPP1 curtailed cancer cell apoptosis in vivo. Moreover, the cytokine directly promoted vascular hyper-permeability independently of vascular endothelial growth factor. In addition, SPP1 of tumor and host origin differentially affected the expression of proinflammatory and angiogenic mediators in the tumor microenvironment. These results suggest that SPP1 of tumor and host origin impact distinct aspects of MPE pathobiology to synergistically promote pleural fluid formation and pleural tumor progression. SPP1 may present an attractive target of therapeutic interventions for patients with MPE.

Microvascular Research, 2010

Reduced lung capillary expression of angiotensin I-converting enzyme (ACE), a key enzyme in cardi... more Reduced lung capillary expression of angiotensin I-converting enzyme (ACE), a key enzyme in cardiovascular pathophysiology, and of caveolin-1, an important regulator of endothelial cell signalling, has been demonstrated in various models of pulmonary arterial hypertension (PAH). We addressed the relationship between PAH and ACE expression in caveolin-1 knockout mice (Cav1(-/-)), which have moderate PAH. Tissue ACE activity was reduced by 50% in lungs from 3-month-old Cav1(-/-) mice compared to wild type (WT). A similar reduction in lung endothelial ACE expression was observed by measuring the lung uptake of (125)I-labeled monoclonal anti-ACE antibody and by quantitative immunohistochemistry. These alterations in ACE are limited to capillary segments of the pulmonary circulation. Functionally, the increase in pulmonary artery pressure (PAP) in response to ACE conversion of angiotensin I to angiotensin II in isolated, perfused mouse lungs was reduced significantly in Cav1(-/-) mice compared to WT. Thus, these complementary approaches demonstrate the dependence of lung microvascular endothelial cell ACE protein expression on caveolin-1 expression and underscore the vital role of caveolin-1-regulated pulmonary vascular homeostasis on endothelial ACE expression and activity. In summary, we have revealed a novel role of caveolin-1 in the regulation of ACE expression in pulmonary capillary endothelial cells. Further understanding of the mechanism by which reduced caveolin-1 expression leads altered pulmonary vascular development, PAH, and reduced ACE expression may have important clinical implications in patients with these severe lung diseases.

Journal of Critical Care, 2013

Intensive Care Medicine, 2012

Intensive Care Medicine, 2013

Your article is protected by copyright and all rights are held exclusively by Springer-Verlag Ber... more Your article is protected by copyright and all rights are held exclusively by Springer-Verlag Berlin Heidelberg and ESICM. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com".

Critical Care, 2013

Introduction: Gene expression profiling was performed via DNA microarrays in leukocytes from crit... more Introduction: Gene expression profiling was performed via DNA microarrays in leukocytes from critically ill trauma patients nonseptic upon admission to the ICU, who subsequently developed either sepsis (n = 2) or severe sepsis and acute respiratory distress syndrome (n = 3). By comparing our results with published expression profiling studies in animal models of sepsis and lung injury, we found aquaporin-1 to be differentially expressed across all studies. Our aim was to determine how the water channel aquaporin-1 is involved in regulating the immune response in critically ill patients during infection acquired in the ICU. Methods: Following the results of the initial genetic screening study, we prospectively followed aquaporin-1 leukocyte expression patterns in patients with ICU-acquired sepsis who subsequently developed septic shock (n = 16) versus critically ill patients who were discharged without developing sepsis (n = 13). We additionally determined aquaporin-1 expression upon lipopolysaccharide (LPS) exposure and explored functional effects of aquaporin-1 induction in polymorphonuclear granulocytes (PMNs).

Critical Care, 2010

Introduction: Activated Protein C (APC), an endogenous anticoagulant, improves tissue microperfus... more Introduction: Activated Protein C (APC), an endogenous anticoagulant, improves tissue microperfusion and endothelial cell survival in systemic inflammatory states such as sepsis, but intravenous administration may cause severe bleeding. We have thus addressed the role of APC delivered locally by inhalation in preventing acute lung injury from alveolar overdistention and the subsequent ventilator-induced lung injury (VILI). We also assessed the effects of APC on the activation status of Extracellular-Regulated Kinase 1/2 (ERK) pathway, which has been shown to be involved in regulating pulmonary responses to mechanical stretch.

Anaesthesia and intensive care

The aim of the study was to calculate the in vitro inspiratory resistance (R(ETT)) of adult endot... more The aim of the study was to calculate the in vitro inspiratory resistance (R(ETT)) of adult endotracheal tubes (ETT), via the end-inspiratory occlusion method, and to apply this method in vivo in order to estimate R(ETT) value in real time. By plotting R(ETT) over inspiratory flow (V) and calculating Rohrer's coefficients of linear and nonlinear resistance, K1 and K2 respectively, we determined the resistive behaviour of each ETT. Peak and plateau pressures were recorded at both proximal and distal sites of the ETT after applying a three-second occlusion under constant flow. Distal pressure was obtained via an intraluminal catheter R(ETT) was calculated as (P(peak) - P(plateau))/(V), at both sites. R(ETT) value resulted from the difference R(proximal) - R(distal). Graph R(ETT) over (V) was plotted and Rohrer's constants were calculated by the method of least squares. For ETTs with inner diameter 9.0, 8.5, 8.0, 7.5, 7.0 and 6.5 mm, K2 was 2.42, 3.05, 4.65, 6.01, 9.17 and 12.8...

B110. GENOMICS, METABOLOMICS, AND EPIGENETICS IN LUNG DISEASE: LATE BREAKING ABSTRACTS, 2012

Critical Care, 2010

We compliment Dr Müller and colleagues [1] for their experiment on the protective role of simvast... more We compliment Dr Müller and colleagues [1] for their experiment on the protective role of simvastatin against ventilator-induced lung injury (VILI). Th eir results are in line with those of a relevant study published recently by our research team; we also showed that pretreatment with statins (specifi cally atorvastatin) attenuates VILI [2]. By synthesizing the fi ndings of the above contributions [1,2], one could make several points.

Intensive Care Medicine, 2008

ABSTRACT Sepsis is a serious disorder with high morbidity and mortality worldwide and an increasi... more ABSTRACT Sepsis is a serious disorder with high morbidity and mortality worldwide and an increasing incidence [1]. Sepsis is the result of an overwhelming and maladaptive response of the host organism to the invasion of pathogenic microorganisms, which generates an uncontrolled and auto-destructive inflammatory process [2]. The septic syndrome carries various degrees of severity, and critically ill patients often develop sepsis-induced acute organ dysfunction (i.e., severe sepsis) and fluid-refractory hypotension (i.e., septic shock). Extensive research performed during the past two decades has greatly improved our understanding of the mechanisms underlying sepsis pathophysiology: Widespread devastating inflammation and microvascular coagulation are common denominators in severe sepsis, while endothelial cell dysfunction appears to be a key determinant in the development of the syndrome [3, 4].

Minerva anestesiologica, 2015

The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant... more The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant and anti-inflammatory pathways. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in the septic process is under investigation. In this study, we assessed the role of sEPCR levels as an early indicator of sepsis development. Plasma sEPCR levels were measured in 59 critically-ill non-septic patients at the time of admission to the intensive care unit (ICU). Multiple logistic regression analysis was performed to identify potential risk factors for sepsis development and Cox-Regression models were fitted for variables to examine their relationship with time to sepsis development. Thirty patients subsequently developed sepsis and 29 did not. At ICU admission, sequential organ failure assessment (SOFA) scores were significantly higher in the subsequent sepsis group as compared to the non sep...

Current opinion in critical care, 2008

Since pulmonary edema from increased endothelial permeability is the hallmark of acute lung injur... more Since pulmonary edema from increased endothelial permeability is the hallmark of acute lung injury, a frequently encountered entity in critical care medicine, the study of endothelial responses in this setting is crucial to the development of effective endothelial-targeted treatments. From the enormous amount of research in the field of endothelial pathophysiology, we have focused on work delineating endothelial alterations elicited by noxious stimuli implicated in acute lung injury. The bulk of the material covered deals with molecular and cellular aspects of the pathogenesis, reflecting current trends in the published literature. We initially discuss pathways of endothelial dysfunction in acute lung injury and then cover the mechanisms of endothelial protection. Several experimental treatments in animal models are presented, which aid in the understanding of the disease pathogenesis and provide evidence for potentially useful therapies. Mechanistic studies have delivered several i...

A66. PRECLINICAL MODELS OF ACUTE LUNG INJURY, 2010

Pulmonary Circulation, 2012

Caveolin-1 is a key regulator of pulmonary endothelial barrier function. Here, we tested the hypo... more Caveolin-1 is a key regulator of pulmonary endothelial barrier function. Here, we tested the hypothesis that caveolin-1 expression is required for ventilator-induced lung injury (VILI). Caveolin-1 gene-disrupted (Cav-1 -/-) and age, sex, and strain-matched wild-type (WT) control mice were ventilated using two protocols: volume-controlled with protective (8 mL/kg) versus injurious (21 mL/Kg) tidal volume for up to 6 hours; and pressure-controlled with protective (airway pressure = 12 cm H 2 O) versus injurious (30 cm H 2 O) ventilation to induce lung injury. Lung microvascular permeability (whole-lung 125 I-albumin accumulation, lung capillary filtration coefficient [K f, c ]) and inflam matory markers (bronchoalveolar lavage [BAL] cytokine levels and neutrophil counts) were measured. We also evaluated histologic sections from lungs, and the time course of Src kinase activation and caveolin-1 phosphorylation. VILI induced a 1.7-fold increase in lung 125 I-albumin accumulation, fourfold increase in K f, c , significantly increased levels of cytokines CXCL1 and interleukin-6, and promoted BAL neutrophilia in WT mice. Lung injury by these criteria was significantly reduced in Cav-1 -/mice but fully restored by i.v. injection of liposome/Cav-1 cDNA complexes that rescued expression of Cav-1 in lung microvessels. As thrombin is known to play a significant role in mediating stretch-induced vascular injury, we observed in cultured mouse lung microvascular endothelial cells (MLECs) thrombin-induced increase in albumin hyperpermeability and phosphorylation of p44/42 MAP kinase in WT but not in Cav-1 -/-MLECs. Thus, caveolin-1 expression is required for mechanical stretch-induced lung inflammation and endothelial hyperpermeability in vitro and in vivo.

Advances in Experimental Medicine and Biology, 2012

The primary function of the mammalian lung is to facilitate diffusion of oxygen to venous blood a... more The primary function of the mammalian lung is to facilitate diffusion of oxygen to venous blood and to ventilate carbon dioxide produced by catabolic reactions within cells. However, it is also responsible for a variety of other important functions, including host defense and production of vasoactive agents to regulate not only systemic blood pressure, but also water, electrolyte and acid-base balance. Caveolin-1 is highly expressed in the majority of cell types in the lung, including epithelial, endothelial, smooth muscle, connective tissue cells, and alveolar macrophages. Deletion of caveolin-1 in these cells results in major functional aberrations, suggesting that caveolin-1 may be crucial to lung homeostasis and development. Furthermore, generation of mutant mice that under-express caveolin-1 results in severe functional distortion with phenotypes covering practically the entire spectrum of known lung diseases, including pulmonary hypertension, fibrosis, increased endothelial permeability, and immune defects. In this Chapter, we outline the current state of knowledge regarding caveolin-1-dependent regulation of pulmonary cell functions and discuss recent research findings on the role of caveolin-1 in various pulmonary disease states, including obstructive and fibrotic pulmonary vascular and inflammatory diseases.

Cytokine, 2014

Widespread endothelial activation and dysfunction often precede clinical sepsis. Several endothel... more Widespread endothelial activation and dysfunction often precede clinical sepsis. Several endotheliumrelated molecules have been investigated as potential biomarkers for early diagnosis and/or prognosis of sepsis, providing different results depending on study designs. Such factors include endothelial adhesion molecules like E-and P-selectin, and the intercellular adhesion molecule-1, vascular endothelial cadherin, growth factors such as Angiopoietin-1 and -2 and vascular endothelial growth factor, as well as von Willebrand factor antigen. We sought to investigate whether circulating biomarkers of endothelial activation/dysfunction measured at ICU admission are associated with subsequent sepsis development.

Vascular pharmacology, 2008

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS... more Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.

Shock, 2012

Aspiration of hydrochloric acid (HCl)-containing gastric juice leads to acute lung injury (ALI) a... more Aspiration of hydrochloric acid (HCl)-containing gastric juice leads to acute lung injury (ALI) and hypoxemic respiratory failure due to an exuberant inflammatory response associated with pulmonary edema from increased vascular and epithelial permeability. The aim of this study was to determine the role and signaling mechanisms of tumor necrosis factor α (TNF-α) in experimental ALI from HCl aspiration using a combination of genetic animal models and pharmacologic inhibition strategies. To this end, HCl was instilled intratracheally to mice, followed by respiratory system elastance measurement, bronchoalveolar lavage, and lung tissue harvesting 24 h after injection. Hydrochloric acid instillation induced an inflammatory response in the lungs of wild-type mice, evidenced as increased bronchoalveolar lavage total cells, neutrophils, and total protein; histologic lung injury score; and respiratory system elastance, whereas TNF-α receptor I mRNA levels were maintained. These alterations could be prevented by pretreatment with etanercept or genetic deletion of the 55-kd TNF-α receptor I, but not by deletion of the TNF-α gene. Hydrochloric acid induced a 6-fold increase in apoptotic, caspase 3-positive cells in lung sections from wild-type mice, which was abrogated in mice lacking TNF-α receptor I. In immunoblotting and immunohistochemistry studies, HCl stimulated signaling via p44/42 and c-Jun N-terminal kinase, which was blocked in TNF-α receptor I knockout mice. In conclusion, ALI induced by HCl requires TNF-α receptor I function and associates with activation of downstream proinflammatory signaling pathways p44/42 and c-Jun N-terminal kinase.

Shock, 2011

Microdialysis (MD) provides the opportunity to monitor tissue metabolic changes. This study aimed... more Microdialysis (MD) provides the opportunity to monitor tissue metabolic changes. This study aimed to describe the kinetics of MD-derived metabolites during the course of critical sepsis, to assess whether these metabolites are useful in grading sepsis severity, and to investigate their prognostic use. To this end, 54 mechanically ventilated septic patients were prospectively studied, out of which 39 had shock. Upon sepsis onset, an MD catheter was inserted into the subcutaneous adipose tissue of the upper thigh. Dialysate samples were analyzed for glucose, pyruvate, lactate, and glycerol. Sampling was performed six times per day for a maximum of 6 days. The daily mean values of MD measurements were calculated for each patient. Arterial blood was analyzed for glucose, lactate, and glycerol concomitantly with dialysate sampling. Blood glucose and tissue glucose levels along with lactate levels were high during the entire study period. Tissue pyruvate and glycerol were also raised, whereas the lactate-pyruvate ratio was preserved. At study entry, patients with septic shock had higher tissue lactate (3.3 vs. 1.9 mmol/L, P = 0.01) and glycerol (340 vs. 169 2mol/L, P = 0.04) levels compared with those without shock. Nonsurvivors had higher tissue lactate (P = 0.008), glycerol (P = 0.004), and pyruvate (P = 0.002) levels than survivors during the whole observation period. Logistic regression analysis showed that age (odds ratio [OR], 1.075; 95% confidence interval [CI], 1.004Y1.150; P = 0.03), Sequential Organ Failure Assessment score on day 1 (OR, 1.550; 95% CI, 1.043Y2.312; P = 0.03), and tissue glycerol on day 1 (OR, 1.007; 95% CI, 1.001Y1.012; P = 0.01) predicted mortality independently. In conclusion, critical sepsis is characterized by high tissue lactate and pyruvate levels and a preserved lactate-pyruvate ratio, suggesting a nonischemic mechanism for raised blood lactate levels. Septic shock is associated with higher tissue lactate and glycerol levels compared with sepsis without shock. Elevated tissue lactate, pyruvate, and glycerol levels are related to poor clinical outcome, with the latter constituting an independent predictor.

Oncogene, 2013

Secreted phosphoprotein-1 (SPP1) promotes cancer cell survival and regulates tumor-associated ang... more Secreted phosphoprotein-1 (SPP1) promotes cancer cell survival and regulates tumor-associated angiogenesis and inflammation, both central to the pathogenesis of malignant pleural effusion (MPE). Here, we examined the impact of tumor-and host-derived SPP1 in MPE formation and explored the mechanisms by which the cytokine exerts its effects. We used a syngeneic murine model of lung adenocarcinoma-induced MPE. To dissect the effects of tumor-versus host-derived SPP1, we intrapleurally injected wild-type and SPP1-knockout C57/BL/6 mice with either wild-type or SPP1-deficient syngeneic lung cancer cells. We demonstrated that both tumor-and host-derived SPP1 promoted pleural fluid accumulation and tumor dissemination in a synergistic manner (Po0.001). SPP1 of host origin elicited macrophage recruitment into the cancer-affected pleural cavity and boosted tumor angiogenesis, whereas tumor-derived SPP1 curtailed cancer cell apoptosis in vivo. Moreover, the cytokine directly promoted vascular hyper-permeability independently of vascular endothelial growth factor. In addition, SPP1 of tumor and host origin differentially affected the expression of proinflammatory and angiogenic mediators in the tumor microenvironment. These results suggest that SPP1 of tumor and host origin impact distinct aspects of MPE pathobiology to synergistically promote pleural fluid formation and pleural tumor progression. SPP1 may present an attractive target of therapeutic interventions for patients with MPE.

Microvascular Research, 2010

Reduced lung capillary expression of angiotensin I-converting enzyme (ACE), a key enzyme in cardi... more Reduced lung capillary expression of angiotensin I-converting enzyme (ACE), a key enzyme in cardiovascular pathophysiology, and of caveolin-1, an important regulator of endothelial cell signalling, has been demonstrated in various models of pulmonary arterial hypertension (PAH). We addressed the relationship between PAH and ACE expression in caveolin-1 knockout mice (Cav1(-/-)), which have moderate PAH. Tissue ACE activity was reduced by 50% in lungs from 3-month-old Cav1(-/-) mice compared to wild type (WT). A similar reduction in lung endothelial ACE expression was observed by measuring the lung uptake of (125)I-labeled monoclonal anti-ACE antibody and by quantitative immunohistochemistry. These alterations in ACE are limited to capillary segments of the pulmonary circulation. Functionally, the increase in pulmonary artery pressure (PAP) in response to ACE conversion of angiotensin I to angiotensin II in isolated, perfused mouse lungs was reduced significantly in Cav1(-/-) mice compared to WT. Thus, these complementary approaches demonstrate the dependence of lung microvascular endothelial cell ACE protein expression on caveolin-1 expression and underscore the vital role of caveolin-1-regulated pulmonary vascular homeostasis on endothelial ACE expression and activity. In summary, we have revealed a novel role of caveolin-1 in the regulation of ACE expression in pulmonary capillary endothelial cells. Further understanding of the mechanism by which reduced caveolin-1 expression leads altered pulmonary vascular development, PAH, and reduced ACE expression may have important clinical implications in patients with these severe lung diseases.

Journal of Critical Care, 2013

Intensive Care Medicine, 2012

Intensive Care Medicine, 2013

Your article is protected by copyright and all rights are held exclusively by Springer-Verlag Ber... more Your article is protected by copyright and all rights are held exclusively by Springer-Verlag Berlin Heidelberg and ESICM. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com".

Critical Care, 2013

Introduction: Gene expression profiling was performed via DNA microarrays in leukocytes from crit... more Introduction: Gene expression profiling was performed via DNA microarrays in leukocytes from critically ill trauma patients nonseptic upon admission to the ICU, who subsequently developed either sepsis (n = 2) or severe sepsis and acute respiratory distress syndrome (n = 3). By comparing our results with published expression profiling studies in animal models of sepsis and lung injury, we found aquaporin-1 to be differentially expressed across all studies. Our aim was to determine how the water channel aquaporin-1 is involved in regulating the immune response in critically ill patients during infection acquired in the ICU. Methods: Following the results of the initial genetic screening study, we prospectively followed aquaporin-1 leukocyte expression patterns in patients with ICU-acquired sepsis who subsequently developed septic shock (n = 16) versus critically ill patients who were discharged without developing sepsis (n = 13). We additionally determined aquaporin-1 expression upon lipopolysaccharide (LPS) exposure and explored functional effects of aquaporin-1 induction in polymorphonuclear granulocytes (PMNs).

Critical Care, 2010

Introduction: Activated Protein C (APC), an endogenous anticoagulant, improves tissue microperfus... more Introduction: Activated Protein C (APC), an endogenous anticoagulant, improves tissue microperfusion and endothelial cell survival in systemic inflammatory states such as sepsis, but intravenous administration may cause severe bleeding. We have thus addressed the role of APC delivered locally by inhalation in preventing acute lung injury from alveolar overdistention and the subsequent ventilator-induced lung injury (VILI). We also assessed the effects of APC on the activation status of Extracellular-Regulated Kinase 1/2 (ERK) pathway, which has been shown to be involved in regulating pulmonary responses to mechanical stretch.