Rho-kinase regulates adhesive and mechanical mechanisms of pulmonary recruitment of neutrophils in abdominal sepsis

Palani, Karzan; Rahman, Milladur; Hasan, Zirak; Zhang, Su; Qi, Zhongquan; Jeppsson, Bengt; Thorlacius, Henrik

doi:10.1016/j.ejphar.2012.02.022

Cited by 16 publications

(7 citation statements)

References 36 publications

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“…Sepsis draws lungs' hyperpermeability and consequent edema, which culminate in respiratory failure. The RhoA/ROCK pathway activation seems to be important in lung inflammation, since the pharmacological inhibition of ROCK decreases neutrophil migration and lung edema in experimental models of sepsis [35,[144][145][146][147]. Besides, researchers found increased levels of apoptosis in septic pulmonary tissue and pulmonary endothelial cells, and ROCK inhibition can prevent this situation [148,149].…”

Section: Rho Proteins and Their Impact On Sepsis Outside The Cardiovascular Systemmentioning

confidence: 99%

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Hahmeyer

Silva-Santos

2021

Cells

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Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models.

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Section: Rho Proteins and Their Impact On Sepsis Outside The Cardiovascular Systemmentioning

confidence: 99%

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Hahmeyer

Silva-Santos

2021

Cells

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“…Herein, we found that expression of Mac-1 was markedly increased on the surface of circulating neutrophils in septic mice. In this context, it is interesting to note that we have previously observed that Rho-kinase regulates both F-actin formation and Mac-1 expression in neutrophils in abdominal sepsis (22). It was therefore of interest to study the role of Rho-kinase signaling in regulating leukocyte-endothelium interactions in the lung in response to local and systemic inflammation.…”

Section: Discussionmentioning

confidence: 98%

“…We have recently observed that Rho-kinase regulates both Mac-1 expression and F-actin formation in neutrophils during abdominal sepsis (22). It was therefore of interest to examine the role of Rho-kinase activity in regulating leukocyte-endothelial cell interactions in the pulmonary microvasculature.…”

Section: Chemokine Levels In the Plasma And Lungmentioning

confidence: 99%

Distinct patterns of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation

Wang

Roller

Slotta

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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The mechanisms of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation remain elusive. Male C57BL/6 mice received lipopolysaccharide (LPS) intrapulmonary (intratracheally, it) or systemically (intravenously, iv) for 1-18 h. Leukocyte responses in lung were analyzed by use of intravital fluorescence microscopy. Plasma and lung levels of CXC chemokines as well as Mac-1 and F-actin expression in leukocytes and bronchoalveolar leukocytes were quantified. Venular leukocyte rolling was markedly increased in response to local LPS but only marginally after systemic LPS. Leukocyte adhesion in venules was enhanced in both groups although adhesion was higher in mice receiving LPS intratracheally compared with LPS intravenously. Systemic LPS caused more leukocytes trapping in capillaries compared with local LPS. The ratio of adherent leukocytes in venules compared with capillaries was higher in response to local LPS, suggesting that leukocytes were more prone to accumulate in venules in local inflammation and in capillaries in systemic inflammation. Systemic LPS triggered higher F-actin formation and Mac-1 expression in leukocytes compared with local LPS. Local and systemic LPS caused similar increases in CXC chemokines in the lung whereas intravenous endotoxin provoked higher levels of CXC chemokines in the circulation. Interestingly, intratracheal LPS increased recruitment of leukocytes in the alveolar space whereas intravenous LPS was ineffective in promoting leukocyte accumulation in the bronchoalveolar space. In conclusion, our data demonstrate that pulmonary microvascular recruitment of leukocytes differs in local and systemic inflammation, which might be related to premature activation and stiffening of circulating leukocytes in endotoxemia.

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“…In terms of viral hemorrhagic fever disease, Eisa-Beygi et al reported the potential feasibility of ROCK blockage as a therapeutic approach for Ebola disease 37 . In septic shock, a sepsis-related mouse model with ROCK inhibitor was used, which also showed a protective effect against sepsis 38 , 39 or lung injury vascular permeability 22 . We applied this ROCK inhibition approach to our in vitro experiment, and our results also support the potential of ROCK inhibitor as a novel treatment for septic shock.…”

Section: Discussionmentioning

confidence: 99%

Impact of plasma 5-hydroxyindoleacetic acid, a serotonin metabolite, on clinical outcome in septic shock, and its effect on vascular permeability

Tanaka

Mori

Sekino

et al. 2021

Sci Rep

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Septic shock is characterized by dysregulated vascular permeability. We hypothesized that the vascular permeability of endothelial cells (ECs) would be regulated by serotonin via serotonin-Rho-associated kinase (ROCK) signaling. We aimed to determine the impact of 5-hydroxyindoleacetic acid (5-HIAA) on septic shock as a novel biomarker. Plasma 5-HIAA levels and disease severity indices were obtained from 47 patients with sepsis. The association between 5-HIAA levels and severity indices was analyzed. Permeability upon serotonin stimulation was determined using human pulmonary microvascular ECs. 5-HIAA were significantly higher in septic shock patients than in patients without shock or healthy controls (p = 0.004). These elevated levels were correlated with severity indexes (SOFA score [p < 0.001], APACHE II [p < 0.001], and PaO2:FiO2 [p = 0.02]), and longitudinally associated with worse clinical outcomes (mechanical ventilation duration [p = 0.009] and ICU duration [p = 0.01]). In the experiment, serotonin increased the permeability of ECs, which was inhibited by the ROCK inhibitor (p < 0.001). Serotonin increases vascular permeability of ECs via ROCK signaling. This suggests a novel mechanism by which serotonin disrupts endothelial barriers via ROCK signaling and causes the pathogenesis of septic shock with a vascular leak. Serotonin serves as a novel biomarker of vascular permeability.

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Rho-kinase regulates adhesive and mechanical mechanisms of pulmonary recruitment of neutrophils in abdominal sepsis

Cited by 16 publications

References 36 publications

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Distinct patterns of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation

Impact of plasma 5-hydroxyindoleacetic acid, a serotonin metabolite, on clinical outcome in septic shock, and its effect on vascular permeability

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