The effects of activated protein C and prostacyclin on arterial oxygenation and protein leakage in the lung and the gut under endotoxaemia in the rat

Dubniks, Maris; Grände, Per‐Olof

doi:10.1111/j.1399-6576.2007.01532.x

Cited by 5 publications

(1 citation statement)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oxygenation and shunt fraction in a sheep model of combined smoke inhalation and bacterial challenge were improved by administration of APC (Maybauer et al ., 2006). Arterial oxygenation only was improved in a rat model of endotoxin‐induced sepsis without effect on pulmonary protein leakage (Dubniks and Grande, 2008). In a polymicrobial sepsis model of caecal ligation and puncture (Richardson et al ., 2008), there was a clear reduction in plasma protein C levels correlated with an increase in macrophage inflammatory protein chemokines and increased PAI‐1 levels.…”

Section: Apc and Acute Lung Injurymentioning

confidence: 99%

Protective mechanisms of activated protein C in severe inflammatory disorders

Neyrinck

Liu

Howard

et al. 2009

British J Pharmacology

View full text Add to dashboard Cite

The protein C system is an important natural anticoagulant mechanism mediated by activated protein C (APC) that regulates the activity of factors VIIIa and Va. Besides well-defined anticoagulant properties, APC also demonstrates anti-inflammatory, anti-apoptotic and endothelial barrier-stabilizing effects that are collectively referred to as the cytoprotective effects of APC. Many of these beneficial effects are mediated through its co-receptor endothelial protein C receptor, and the protease-activated receptor 1, although exact mechanisms remain unclear and are likely pleiotropic in nature. Increased insight into the structure-function relationships of APC facilitated design of APC variants that conserve cytoprotective effects and reduce anticoagulant features, thereby attenuating the risk of severe bleeding with APC therapy. Impairment of the protein C system plays an important role in acute lung injury/acute respiratory distress syndrome and severe sepsis. The pathophysiology of both diseases states involves uncontrolled inflammation, enhanced coagulation and compromised fibrinolysis. This leads to microvascular thrombosis and organ injury. Administration of recombinant human APC to correct the dysregulated protein C system reduced mortality in severe sepsis patients (PROWESS trial), which stimulated further research into its mechanisms of action. Several other clinical trials evaluating recombinant human APC have been completed, including studies in children and less severely ill adults with sepsis as well as a study in acute lung injury. On the whole, these studies have not supported the use of APC in these populations and challenge the field of APC research to search for additional answers.

show abstract

Section: Apc and Acute Lung Injurymentioning

confidence: 99%

Protective mechanisms of activated protein C in severe inflammatory disorders

Neyrinck

Liu

Howard

et al. 2009

British J Pharmacology

View full text Add to dashboard Cite

show abstract

Barrier Enhancing Signals in Pulmonary Edema

Birukov

Zebda

Birukova

2013

Comprehensive Physiology

View full text Add to dashboard Cite

Increased endothelial permeability and reduction of alveolar liquid clearance capacity are two leading pathogenic mechanisms of pulmonary edema, which is a major complication of acute lung injury, severe pneumonia, and acute respiratory distress syndrome, the pathologies characterized by unacceptably high rates of morbidity and mortality. Besides the success in protective ventilation strategies, no efficient pharmacological approaches exist to treat this devastating condition. Understanding of fundamental mechanisms involved in regulation of endothelial permeability is essential for development of barrier protective therapeutic strategies. Ongoing studies characterized specific barrier protective mechanisms and identified intracellular targets directly involved in regulation of endothelial permeability. Growing evidence suggests that, although each protective agonist triggers a unique pattern of signaling pathways, selected common mechanisms contributing to endothelial barrier protection may be shared by different barrier protective agents. Therefore, understanding of basic barrier protective mechanisms in pulmonary endothelium is essential for selection of optimal treatment of pulmonary edema of different etiology. This article focuses on mechanisms of lung vascular permeability, reviews major intracellular signaling cascades involved in endothelial monolayer barrier preservation and summarizes a current knowledge regarding recently identified compounds which either reduce pulmonary endothelial barrier disruption and hyperpermeability, or reverse preexisting lung vascular barrier compromise induced by pathologic insults.

show abstract