Mechanisms regulating endothelial cell barrier function

Stevens, Troy; Garcia, Joe G.N.; Shasby, D. Michael; Bhattacharya, Jahar; Malik, Asrar B.

doi:10.1152/ajplung.2000.279.3.l419

Cited by 221 publications

(222 citation statements)

References 42 publications

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“…Capillary function is decreased, which prevents oxygen uptake and increases endothelial permeability [68]. e latter changes produce edema with protein-rich uid [69]. In the lungs, vascular epithelium injury produces interstitial and alveolar edema and the phagocytic cells retained in microcirculation increase the injury to alveolar membranes [69].…”

Section: Organ Dysfunctionmentioning

confidence: 99%

“…e latter changes produce edema with protein-rich uid [69]. In the lungs, vascular epithelium injury produces interstitial and alveolar edema and the phagocytic cells retained in microcirculation increase the injury to alveolar membranes [69]. In the kidney, factors such as systemic hypotension, renal vasoconstriction and release of cytokines produce acute tubular necrosis and renal injury [70].…”

Section: Organ Dysfunctionmentioning

confidence: 99%

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Sepsis, mitochondrial failure and multiple organ dysfunction

Dúran-Bedolla

Oca-Sandoval²,

Saldaña-Navor³

et al. 2014

CIM

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Purpose: e purpose of this review is to consider the state of oxidative stress, failure of the antioxidant systems and mitochondrial failure as the main physiopathological mechanisms leading to multiple organ dysfunction during sepsis.Principal ndings: Sepsis is a clinical syndrome caused by a severe infection that triggers an exaggerated in ammatory response. Involved in the pathogenesis of sepsis are the activation of in ammatory, immune, hormonal, metabolic and bioenergetic responses. One of the pivotal factors in these processes is the increase of reactive species accompanied by the failure of the antioxidant systems, leading to a state of irreversible oxidative stress and mitochondrial failure.In a physiological state, reactive species and antioxidant systems are in redox balance. e loss of this balance during both chronic and infectious diseases leads to a state of oxidative stress, which is considered to be the greatest promoter of a systemic in ammatory response.e loss of the redox balance, together with a systemic in ammatory response during sepsis, can lead to progressive and irreversible mitochondrial failure, energy depletion, hypoxia, septic shock, severe sepsis, multiple organ dysfunction and death of the patient. Conclusion:Knowledge of the molecular processes associated with the development of oxidative stress should facilitate the development of e ective therapies and better prognosis for patients with sepsis and organ dysfunction.

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Section: Organ Dysfunctionmentioning

confidence: 99%

Section: Organ Dysfunctionmentioning

confidence: 99%

Sepsis, mitochondrial failure and multiple organ dysfunction

Dúran-Bedolla

Oca-Sandoval²,

Saldaña-Navor³

et al. 2014

CIM

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show abstract

“…This series of events could be shown in vitro but also in anoxic/reperfused ex vivo experiments (Zou and Bachschmid, 1999d This topic has been subject of intense research and not all relevant literature can be listed here. The reader is referred to excellent reviews for further information (Stevens et al, 2000;Lum and Roebuck, 2001;Goligorsky et al, 2000;Vanhoutte, 2002).…”

Section: Introductionmentioning

confidence: 99%

Superoxide as a Messenger of Endothelial Function

Ullrich

Bachschmid²

2000

Biochemical and Biophysical Research Communications

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“…In sepsis-related lung injury (6), it is the release of oxidative metabolites by penetrant leukocytes that causes lung tissue damage. In vitro studies (1) have implicated protein kinases such as myosin light-chain kinase (MLCK) and Rho kinase in the regulation of EC barrier function through their direct regulation of the phosphorylation state of myosin light chains and the intracellular cytoskeletal contractionrelaxation cycles.…”

mentioning

confidence: 99%

Protein kinase involved in lung injury susceptibility: Evidence from enzyme isoform genetic knockout and in vivo inhibitor treatment

Wainwright

Rossi

Schavocky

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

133

147

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Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event in the pathophysiology, with intracellular protein kinases as critical mediators of normal physiology and possible targets for drug discovery. The 210,000 molecular weight myosin light chain kinase (MLCK210, also called EC MLCK because of its abundance in EC) is hypothesized to be important for EC barrier function and might be a potential therapeutic target. To test these hypotheses directly, we made a selective MLCK210 knockout mouse that retains production of MLCK108 (also called smooth-muscle MLCK) from the same gene. The MLCK210 knockout mice are less susceptible to ALI induced by i.p. injection of the endotoxin lipopolysaccharide and show enhanced survival during subsequent mechanical ventilation. Using a complementary chemical biology approach, we developed a new class of small-molecule MLCK inhibitor based on the pharmacologically privileged aminopyridazine and found that a single i.p. injection of the inhibitor protected WT mice against ALI and death from mechanical ventilation complications. These convergent results from two independent approaches demonstrate a pivotal in vivo role for MLCK in susceptibility to lung injury and validate MLCK as a potential drug discovery target for lung injury.C urrent hypotheses (1, 2) identify dysfunction of the endothelial cell (EC) layer as a cardinal event in the pathophysiology of multiple medical conditions, including sepsis. The mortality associated with sepsis alone is similar (3) to that of acute myocardial infarction (MI). In contrast to MI, available therapies are limited for the treatment of sepsis and its associated tissue injuries (3, 4). Mechanical ventilation is often required for the support of patients with sepsis but is itself associated with additional, iatrogenic pulmonary injury that also appears to involve EC barrier dysfunction (5). Recent progress in the use of controlled ventilator strategies, such as positive end-expiratory pressure (PEEP), lessens the potential for ventilator-induced lung injury (VILI), but a need still exists for therapies that would prevent this clinical complication (5). Most recently, in vitro studies have linked a variety of EC signal transduction pathways to the physiological mechanisms of EC barrier function and identified several endothelial protein kinases as potential drug discovery targets (1). However, the integration of the knowledge regarding in vitro signal transduction pathways with in vivo pathophysiology related to compromised EC barrier function and the validation of potential EC therapeutic targets have not occurred.Homeostasis and resistance to tissue injury are maintained by a balance between intracellular EC cytoskeletal contractionrelaxation cycles and modulation of EC extracellular adhesion properties, whi...

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Mechanisms regulating endothelial cell barrier function

Cited by 221 publications

References 42 publications

Sepsis, mitochondrial failure and multiple organ dysfunction

Sepsis, mitochondrial failure and multiple organ dysfunction

Superoxide as a Messenger of Endothelial Function

Protein kinase involved in lung injury susceptibility: Evidence from enzyme isoform genetic knockout and in vivo inhibitor treatment

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