Maraviroc-Mediated Lung Protection following Trauma-Hemorrhagic Shock

Liu, Fu-Chao; Zheng, Chih-Wen; Yu, Huang-Ping

doi:10.1155/2016/5302069

Cited by 4 publications

(6 citation statements)

References 41 publications

(56 reference statements)

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“…Severe trauma with hemorrhagic shock, as modeled here in mice, can lead to rapid lung injury and dysfunction [ 57 , 58 ]. To assess the impact of the IL33/ILC2/IL5/neutrophil pathway on lung changes 6 hours after HS/T in mice lacking IL33 or ILC2 or in which IL5 had been neutralized ( Fig 8 ).…”

Section: Resultsmentioning

confidence: 99%

IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model

Guardado

Hoffman

et al. 2017

PLoS Med

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BackgroundThe immunosuppression and immune dysregulation that follows severe injury includes type 2 immune responses manifested by elevations in interleukin (IL) 4, IL5, and IL13 early after injury. We hypothesized that IL33, an alarmin released early after tissue injury and a known regulator of type 2 immunity, contributes to the early type 2 immune responses after systemic injury.Methods and findingsBlunt trauma patients admitted to the trauma intensive care unit of a level I trauma center were enrolled in an observational study that included frequent blood sampling. Dynamic changes in IL33 and soluble suppression of tumorigenicity 2 (sST2) levels were measured in the plasma and correlated with levels of the type 2 cytokines and nosocomial infection. Based on the observations in humans, mechanistic experiments were designed in a mouse model of resuscitated hemorrhagic shock and tissue trauma (HS/T). These experiments utilized wild-type C57BL/6 mice, IL33-/- mice, B6.C3(Cg)-Rorasg/sg mice deficient in group 2 innate lymphoid cells (ILC2), and C57BL/6 wild-type mice treated with anti-IL5 antibody.Severely injured human blunt trauma patients (n = 472, average injury severity score [ISS] = 20.2) exhibited elevations in plasma IL33 levels upon admission and over time that correlated positively with increases in IL4, IL5, and IL13 (P < 0.0001). sST2 levels also increased after injury but in a delayed manner compared with IL33. The increases in IL33 and sST2 were significantly greater in patients that developed nosocomial infection and organ dysfunction than similarly injured patients that did not (P < 0.05). Mechanistic studies were carried out in a mouse model of HS/T that recapitulated the early increase in IL33 and delayed increase in sST2 in the plasma (P < 0.005). These studies identified a pathway where IL33 induces ILC2 activation in the lung within hours of HS/T. ILC2 IL5 up-regulation induces further IL5 expression by CXCR2+ lung neutrophils, culminating in early lung injury. The major limitations of this study are the descriptive nature of the human study component and the impact of the potential differences between human and mouse immune responses to polytrauma. Also, the studies performed did not permit us to make conclusions about the impact of IL33 on pulmonary function.ConclusionsThese results suggest that IL33 may initiate early detrimental type 2 immune responses after trauma through ILC2 regulation of neutrophil IL5 production. This IL33–ILC2–IL5–neutrophil axis defines a novel regulatory role for ILC2 in acute lung injury that could be targeted in trauma patients prone to early lung dysfunction.

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Section: Resultsmentioning

confidence: 99%

IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model

Guardado

Hoffman

et al. 2017

PLoS Med

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“…It has also been observed that MVC decreases mucosal inflammation (30), VCAM-1 (31), T cell infiltration, neuroinflammation (32) and endothelial dysfunction (33). Regarding the lung, a model of induced hemorrhagic shock in rats reported that MVC has a protective role against pulmonary damage (34). All the aforementioned, along with the broad safety range of MVC, good tolerance an low incidence of adverse effects (35) makes it an excellent candidate to be used as a modulator of the dysregulated immune response in COVID-19.…”

Section: Introductionmentioning

confidence: 99%

A Randomized, Controlled Study on the Safety and Efficacy of Maraviroc and/or Favipiravir vs Currently Used Therapy in Severe COVID-19 Adults. “COMVIVIR” Trial.

Pérez-García

Villalobos-Osnaya

Hernández-Medel

et al. 2021

Preprint

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Multiple studies have established that hyperinflammatory response induced by SARS CoV-2 is a main cause of complications and death in infected subjects. Such dysfunctional immune response has been described as a dysregulated and exacerbated production of cytokines and chemokines that attracts and activates inflammatory cells, which start and sustain pulmonary and systemic damage, thus causing complications that lead to multi organ failure and death. Therefore, we suggest that blocking key inflammation receptors could help to reduce migration and activation of T cells, monocytes/macrophages and neutrophils, thus mitigating the cytokine dysregulation and averting severe complications and death. Importantly, the optimum treatment for COVID-19 severe patients should combine a modulator of the immune response plus a direct antiviral drug against SARS-CoV-2, in order to address both the hyperinflammatory effects of the immune dysregulation and the viral load. Methods: Maraviroc (MVC), a CCR5 antagonist, and Favipiravir (FPV), an antiviral, will be evaluated single and combined, added to the treatment currently used at the Hospital General de México Dr. Eduardo Liceaga for severe COVID-19 patients. One hundred patients will be allocated in four arms [Current treatment only (CT), CT+MVC, CT+FPV, CT+MVC+FPV]. Percentage of patients free of mechanical ventilation or death at day 28, immunophenotyping and viral load will be compared between groups. Discussion: New immune focused therapies are targeting strong inflammation mediators such as IL-6 and IL1-β; nevertheless, to our best knowledge, only one study explores chemotaxis control. The use of a drug therapy that addresses both the regulation of the immune response and the inhibition of viral replication could at the same time, help to alleviate the hyperinflammatory condition and reduce the time of the viral clearance process, therefore improving treatment outcomes.

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“…Based on its complex pathophysiological mechanisms, the interaction of various factors, such as in ammatory damage [2,3]. and blood-brain barrier destruction, [4].…”

Section: Introdutionmentioning

confidence: 99%

“…Acute ischemic stroke is the most common cerebrovascular event with high morbidity and mortality[1].. Based on its complex pathophysiological mechanisms, the interaction of various factors, such as in ammatory damage [2,3]. and blood-brain barrier destruction, [4].…”

Section: Introdutionmentioning

confidence: 99%

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Maraviroc, An Inhibitor of Chemokine Receptor Type 5, Alleviates Neuroinflammatory Response after Cerebral Ischemia/Reperfusion Injury via Regulating JNK Signaling

Chen¹,

Cao²,

Guo³

et al. 2021

Preprint

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Neuroinflammation is a key factor that contributes to the secondary injury after cerebral ischemia/reperfusion (CI/R) injury. Chemokine receptor type 5(CCR5) has shown its pro-inflammatory effects during central nervous system (CNS) diseases. However, the role of CCR5 in CI/R injury is still unclear. In this study, we administered maraviroc (MVC,APEXBIO,UK-427857), a CCR5 antagonist, to the middle cerebral artery occlusion(MCAO) mice. In vivo studies showed that MVC was successively intraperitoneally (i.p.) with different doses (5, 20, or 50 mg/kg body weight) for 3 days after mice MCAO. MVC showed its neuroprotective effects in alleviating neurological deficits and infarct volumes after MCAO. The level of apoptosis and inflammation were remarkably decreased by MVC treatment after CI/R injury. Subsequently, primary microglia were stimulated with different doses of MVC (0.2, 2, 20 or 200nM) for 12h after oxygen-glucose deprivation/reoxygenation model (OGD/R) in vitro. MVC significantly increased the viability of primary microglia after (OGD/R). The expression of pro-inflammatory cytokines (IL-1β and IL-6) in microglia were down-regulated by MVC treatment. Mechanistically, MVC also inhibited the secretion of IL-1β and IL-6 by microglia after OGD stimulation. Furthermore, the key components of NF-κB pathway were measured in vivo and in vitro after MCAO and OGD. MVC significantly inhibited the activity of NF-κB pathway in the above pathological environments. Finally, our data indicated that MVC treatment decreased the activation of JNK signaling pathway after CI/R injury in vivo and in vitro. The JNK activator anisomycin (AN，Beyotime，SC0132-5mg) reversed the neuroprotective effects of MVC, indicating that the JNK pathway is involved in the anti-inflammatory and anti-apoptotic mechanisms of MVC in CI/R injury. Our data demonstrated that CCR5 inhibition exhibits neuroprotective effects after CI/R injury. MVC, which is widely used for HIV treatment by its anti-virus effect, is a potential drug for the treatment of ischemic stroke in the future clinical trials.

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Maraviroc-Mediated Lung Protection following Trauma-Hemorrhagic Shock

Cited by 4 publications

References 41 publications

IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model

IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model

A Randomized, Controlled Study on the Safety and Efficacy of Maraviroc and/or Favipiravir vs Currently Used Therapy in Severe COVID-19 Adults. “COMVIVIR” Trial.

Maraviroc, An Inhibitor of Chemokine Receptor Type 5, Alleviates Neuroinflammatory Response after Cerebral Ischemia/Reperfusion Injury via Regulating JNK Signaling

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