Rac1 signaling regulates sepsis-induced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation

Hwaiz, Rundk; Hasan, Zirak; Rahman, Milladur; Zhang, Su; Palani, Karzan; Syk, Ingvar; Jeppsson, Bengt; Thorlacius, Henrik

doi:10.1016/j.jss.2013.02.045

Cited by 31 publications

(30 citation statements)

References 42 publications

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“…Our study also suggests that activation of the inflammasome-IL-1β axis is, at least in part, controlled by Rac1 signaling in hyperoxia-induced neonatal lung injury, because we found that treatment with NSC23766, a specific Rac1 inhibitor, significantly downregulated the expression of the inflammasome proteins and the activation of IL-1β in hyperoxia-exposed lungs. Previous studies using other models of inflammatory lung injury appear to support our findings, as Rac1 inhibition with NSC23766 has been reported to decrease the macrophage/neutrophil infiltration and lung injury induced by lipopolysaccharide, streptococcal M1 protein, or sepsis, and also the expression of NLRP3 and active IL-1β in C. pneumonia -infected human mononuclear cells [11,14,15]. Thus, our study has revealed a novel mechanism by which Rac1 signaling regulates the hyperoxia-induced inflammatory response in the neonatal lung.…”

Section: Discussionsupporting

confidence: 88%

“…Recent studies showed that Rac1 controls the NLRP3 inflammasome-mediated processing of pro-IL-1β in Chlamydophila pneumoniae- infected mononuclear cells [11]. In fact, treatment with NSC23766, a specific Rac1 inhibitor, decreases leukocyte infiltration and lung injury in animal models [14,15]. Rac1 also regulates the expression of connective tissue growth factor (CTGF), which is a key factor in the pathogenesis of pulmonary vascular remodeling and fibrosis [16].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Rac1 Signaling Downregulates Inflammasome Activation and Attenuates Lung Injury in Neonatal Rats Exposed to Hyperoxia

et al. 2016

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Background: Inflammatory injury, particularly the production of active interleukin (IL)-1β plays a major role in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. The release of active IL-1β is controlled by posttranscriptional modifications of its proform (pro-IL-1β) through the inflammasome. Rac1 is a member of the Rho family of GTPases that regulate the inflammatory process. Objective: This study tested the hypothesis that Rac1 signaling increases inflammasome activation that results in damaging inflammation, and that the inhibition of Rac1 signaling prevents lung injury, by inhibiting inflammasome activation in a newborn rat model of BPD induced by hyperoxia. Methods: Newborn rat pups were exposed to room air or hyperoxia (85% O₂) and received daily intraperitoneal injections of placebo (normal saline) or NSC23766, a specific Rac1 inhibitor, for 10 days. The effects on lung inflammation, alveolarization, vascular development, vascular remodeling, right ventricular systolic pressure, and right ventricular hypertrophy (RVH) were then assessed. Results: Hyperoxia exposure upregulated Rac1 and increased the production of active IL-1β, which was accompanied by increasing expression of the inflammasome. In addition, hyperoxia induced the pathological hallmarks of BPD. However, treatment with NSC23766 significantly decreased inflammasome activation and macrophage infiltration, improved alveolar and vascular development, and reduced pulmonary vascular remodeling and RVH. Conclusion: These results indicate that Rac1 signaling regulates the expression of the inflammasome and plays a pivotal role in the pathogenesis of hyperoxia-induced neonatal lung injury. Therefore, targeting Rac1 signaling may provide a novel strategy to prevent and treat BPD in preterm infants.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Inhibition of Rac1 Signaling Downregulates Inflammasome Activation and Attenuates Lung Injury in Neonatal Rats Exposed to Hyperoxia

et al. 2016

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“…[14][15][16] Rac1 is a ubiquitously expressed signal transducer regulating numerous processes related to inflammatory reactions, such as cell adhesion, chemotaxis, vascular permeability, and cytoskeletal reorganization. 17,18 Rac1 has been shown to be expressed in platelets and recent studies have demonstrated that Rac1 is essential for lamellipodia formation, granule secretion, clot retraction, and phospholipase Cg2 activation in platelets. [19][20][21][22][23][24] Moreover, targeting Rac1 signaling has been demonstrated to exert anti-inflammatory effects in models of reperfusion injury, endotoxemia, acute pancreatitis, and sepsis.…”

mentioning

confidence: 99%

“…[19][20][21][22][23][24] Moreover, targeting Rac1 signaling has been demonstrated to exert anti-inflammatory effects in models of reperfusion injury, endotoxemia, acute pancreatitis, and sepsis. 17,[25][26][27] Based on the findings that Rac1 regulates pleiotropic functions of platelets and that Rac1 appears to have an important role in diverse models of inflammation, we hypothesized in the present study that Rac1 might be involved in the regulation of platelet shedding of CD40L in abdominal sepsis.…”

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confidence: 99%

Rac1 regulates platelet shedding of CD40L in abdominal sepsis

Hwaiz

Rahman

Zhang

et al. 2014

Laboratory Investigation

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Matrix metalloproteinase-9 (MMP-9) regulates platelet shedding of CD40L in abdominal sepsis. However, the signaling mechanisms controlling sepsis-induced shedding of CD40L from activated platelets remain elusive. Rac1 has been reported to regulate diverse functions in platelets; we hypothesized herein that Rac1 might regulate platelet shedding of CD40L in sepsis. The specific Rac1 inhibitor NSC23766 (N6-[2-[[4-(diethylamino)-1-methylbutyl] amino]-6-methyl-4-pyrimidinyl]-2 methyl-4, 6-quinolinediamine trihydrochloride) was administered to mice undergoing cecal ligation and puncture (CLP). Levels of CD40L and MMP-9 in plasma, platelets, and neutrophils were determined by use of ELISA, western blot, and confocal microscopy. Platelet depletion abolished the CLP-induced increase in plasma levels of CD40L. Rac1 activity was significantly increased in platelets from septic animals. Administration of NSC23766 abolished the CLP-induced enhancement of soluble CD40L levels in the plasma. Moreover, Rac1 inhibition completely inhibited proteinase-activated receptor-4-induced surface mobilization and secretion of CD40L in isolated platelets. CLP significantly increased plasma levels of MMP-9 and Rac1 activity in neutrophils. Treatment with NSC23766 markedly attenuated MMP-9 levels in the plasma from septic mice. In addition, Rac1 inhibition abolished chemokine-induced secretion of MMP-9 from isolated neutrophils. Finally, platelet shedding of CD40L was significantly reduced in response to stimulation with supernatants from activated MMP-9-deficient neutrophils compared with supernatants from wild-type neutrophils, indicating a direct role of neutrophil-derived MMP-9 in regulating platelet shedding of CD40L. Our novel data suggest that sepsis-induced platelet shedding of CD40L is dependent on Rac1 signaling. Rac1 controls surface mobilization of CD40L on activated platelets and MMP-9 secretion from neutrophils. Thus, our findings indicate that targeting Rac1 signaling might be a useful way to control pathologic elevations of CD40L in the systemic circulation in abdominal sepsis.

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“…Mesenteric arteries were isolated from streptozotocin‐treated mice and their control (vehicle‐injected) littermates after IP injection of NSC23766 (5 mg/kg, as previously described),20, 21 at different time points (6, 12, 24, 36, 48, and 96 hours after injection) to perform vascular reactivity studies (Figure 1A through 1F). No effects on blood glucose levels and body weight were found after NSC23766 treatment in both control and streptozotocin‐treated mice (Table S2).…”

Section: Resultsmentioning

confidence: 99%

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus

Schiattarella

Carrizzo

Ilardi

et al. 2018

JAHA

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BackgroundVascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho‐related GTPase protein, Rac1, can influence both endothelial and platelet function and might represent a potential novel therapeutic target in diabetes mellitus.Methods and ResultsWe used both in vitro and ex vivo approaches to test the effects of pharmacological inhibition of Rac1 during hyperglycemic condition. We evaluated the effect of NSC23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC23766 protects from hyperglycemia‐induced endothelial dysfunction, restoring NO levels, and reduces oxidative stress generated by nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, we identified Rho‐associated coiled‐coil serine/threonine kinase‐1 as a downstream target of Rac1. Moreover, we reported that during hyperglycemic conditions, human platelets showed hyperactivation of Rac1 and impaired NO release, which were both partially restored after NSC23766 treatment. Finally, we characterized the antiplatelet effect of NSC23766 during hyperglycemic conditions, demonstrating the additional role of Rac1 inhibition in reducing platelet aggregation in diabetic patients treated with common antiplatelet drugs.ConclusionsOur data suggest that the pharmacological inhibition of Rac1 could represent a novel therapeutic strategy to reduce endothelial dysfunction and platelet hyperaggregation in diabetes mellitus.

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Rac1 signaling regulates sepsis-induced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation

Cited by 31 publications

References 42 publications

Inhibition of Rac1 Signaling Downregulates Inflammasome Activation and Attenuates Lung Injury in Neonatal Rats Exposed to Hyperoxia

Inhibition of Rac1 Signaling Downregulates Inflammasome Activation and Attenuates Lung Injury in Neonatal Rats Exposed to Hyperoxia

Rac1 regulates platelet shedding of CD40L in abdominal sepsis

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus

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