Ischaemic stroke in mice induces lung inflammation but not acute lung injury

Austin, Victoria; Ku, Jacqueline M; Miller, Alyson A.; Vlahos, Ross

doi:10.1038/s41598-019-40392-1

Cited by 23 publications

(21 citation statements)

References 35 publications

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“…These changes were unlikely due to the spontaneous bacterial infection that reported in other studies . Consistent with our observations, recent studies have also shown that severe ischemic stroke in mice does not cause spontaneous bacterial infection . Using tMCAO model, Stanley et al showed that SAP is caused by the translocation and dissemination of commensal bacteria from the intestinal tracts to lungs, and SAP does not occur in mice housed in a germ‐free environment.…”

Section: Discussionsupporting

confidence: 92%

“…3,15 Consistent with our observations, recent studies have also shown that severe ischemic stroke in mice does not cause spontaneous bacterial infection. 23 Using tMCAO model, Stanley et al 15 showed that SAP is caused by the translocation and dissemination of commensal bacteria from the intestinal tracts to lungs, and SAP does not occur in mice housed in a germ-free environment. These observations strongly suggest that the incidence of SAP is determined by the composition of gut microbiota, and this speculation is further supported by the fact that mice with different genetic backgrounds develop SAP with various severity.…”

Section: Discussionmentioning

confidence: 99%

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Ischemic stroke alters immune cell niche and chemokine profile in mice independent of spontaneous bacterial infection

Farris

Monaghan

Zheng

et al. 2019

Immunity Inflam & Disease

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Introduction Stroke‐associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multifactorial in nature, stroke‐induced immunosuppression plays a key role in the development of SAP. Previous studies using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that focal ischemic stroke induction results in functional defects of lymphocytes in the spleen, thymus, and peripheral blood, leading to spontaneous bacterial infection in the lungs without inoculation. However, how ischemic stroke alters immune cell niche and the expression of cytokines and chemokines in the lungs has not been fully characterized. Methods Ischemic stroke was induced in mice by tMCAO. Immune cell profiles in the brain and the lungs at 24‐ and 72‐hour time points were compared by flow cytometric analysis. Cytokine and chemokine expression in the lungs were determined by multiplex bead arrays. Tissue damage and bacterial burden in the lungs following tMCAO were evaluated. Results Ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b+ dendritic cells, but reduces the percentage of CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and eosinophils in the lungs. The alteration of immune cell niche in the lungs coincides with a significant reduction in the levels of multiple chemokines in the lungs, including CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. Spontaneous bacterial infection and tissue damage following tMCAO, however, were not observed. Conclusion This is the first report to demonstrate a significant reduction of lymphocytes and multiple proinflammatory chemokines in the lungs following ischemic stroke in mice. These findings suggest that ischemic stroke directly impacts pulmonary immunity.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Ischemic stroke alters immune cell niche and chemokine profile in mice independent of spontaneous bacterial infection

Farris

Monaghan

Zheng

et al. 2019

Immunity Inflam & Disease

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“…The increase of ACE2 levels within 24 h of brain injury suggests fast kinetics of signaling to induce protein expression changes in the lungs. The molecular mechanisms underlying this response in the lungs after transient MCAO are currently unclear, but, based on our data and related studies of others increased post-stroke lung inflammation might be a possible explanation (Austin et al, 2019). Physiologically, the augmented ACE2 levels in inflamed lungs after brain ischemia may help to counterbalance the subsequent inflammatory lung injury (Imai et al, 2005).…”

Section: Discussionmentioning

confidence: 58%

“…In addition, stroke patients may present signs of severe immunosuppression and inflammation that often lead to hospital-acquired respiratory infections (Shi et al, 2018). A recent study by Austin et al has demonstrated an increased number of mononuclear granulocytes in bronchoalveolar lavage fluid and higher IL-1 expression in lung tissue of mice that were subjected to ischemia-induced brain injury (Austin et al, 2019). In this respect, it is highly conspicuous that a plethora of clinical studies identified stroke as one of the most significant risk factors for a severe course of COVID-19 in humans (Bravi, 2020;Khawaja, 2020;Pigoga, 2020;Ssentongo, 2020).…”

Section: Introductionmentioning

confidence: 99%

Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

Singh

Beer

Kraus

et al. 2020

Preprint

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Highlights:Brain tissue injury increases ACE2 levels in the lungs Brain injury induces pro-inflammatory cytokine expression in the lungs Brain injury causes parenchymal inflammation and systemic lymphopeniaAbstract Background: The newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated.Methods: Mice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1β were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry.Results: Strikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1 in the lungs. Higher gene expression of cytokines IL-6 and IL-1 was found in ischemic brain hemispheres and a reduced number of Tlymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression. Conclusions:We demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions.

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“…Adrenergic and the HPA axis pathways act synergistically to induce splenic atrophy and natural killer (NK) cell deficiency in the periphery via coordinated effects of NE and GCs [4]. Moreover, ischemic stroke may cause a significant increase in bronchoalveolar lavage fluid macrophages and neutrophils and whole lung tissue proinflammatory IL-1β mRNA expression in experimental mice [5]. IL-1β is known to be involved in the development of acute lung injury (ALI) and/or acute respiratory distress syndrome and has been shown to be one of the most biologically active cytokines in ALI [5].…”

mentioning

confidence: 99%

Mechanical ventilation in patients with acute ischemic stroke: from pathophysiology to clinical practice

2020

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Ischaemic stroke in mice induces lung inflammation but not acute lung injury

Cited by 23 publications

References 35 publications

Ischemic stroke alters immune cell niche and chemokine profile in mice independent of spontaneous bacterial infection

Ischemic stroke alters immune cell niche and chemokine profile in mice independent of spontaneous bacterial infection

Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

Mechanical ventilation in patients with acute ischemic stroke: from pathophysiology to clinical practice

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