Neutrophil-Derived IL-6 Limits Alveolar Barrier Disruption in Experimental Ventilator-Induced Lung Injury

Wolters, Paul J.; Wray, Charlie M; Sutherland, Robert M.; Kim, Sophia S.; Koff, J.L.; Mao, Ying; Frank, James A.

doi:10.4049/jimmunol.0801323

Cited by 50 publications

(53 citation statements)

References 27 publications

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“…IL-6 is predominantly proinflammatory, and is often correlated with poor ARDS outcomes in humans (44). However, its effects are pleiotropic, and IL-6 can even be lung-protective in some lung injury models (45)(46)(47). Therefore, without further research, we cannot determine whether the relationship between elevated IL-6 concentrations and improved cardiopulmonary function in A77-treated mice is correlative or causative.…”

Section: Discussionmentioning

confidence: 87%

Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice

Aeffner¹,

Bratasz

Flaño

et al. 2012

Am J Respir Cell Mol Biol

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Section: Discussionmentioning

confidence: 87%

Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice

Aeffner¹,

Bratasz

Flaño

et al. 2012

Am J Respir Cell Mol Biol

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“…However, despite well-documented involvement of IL-6 in the mechanisms of VILI-associated inflammation and EC barrier dysfunction, also shown in this study, the idea of IL-6 blockage as a therapeutic option for VILI treatment should be considered with caution. Injection of IL-6 blocking antibodies in mice after ventilator induced lung injury significantly increased rates of BAL albumin flux (38). Surprisingly, IL-6 overexpression even protected mice against hyperoxic lung injury by regulating Bax and reducing apoptosis through a PI-3 kinase pathway (22).…”

Section: Discussionmentioning

confidence: 98%

Stimulation of Rho signaling by pathologic mechanical stretch is a “second hit” to Rho-independent lung injury induced by IL-6

Birukova

Tian

Meliton

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Birukova AA, Tian Y, Meliton A, Leff A, Wu T, Birukov KG. Stimulation of Rho signaling by pathologic mechanical stretch is a "second hit" to Rho-independent lung injury induced by IL-6. Am J Physiol Lung Cell Mol Physiol 302: L965-L975, 2012. First published February 17, 2012 doi:10.1152/ajplung.00292.2011.-Most patients with acute lung injury (ALI) and acute respiratory distress syndrome of septic and nonseptic nature require assisted ventilation with positive pressure, which at suboptimal range may further exacerbate lung dysfunction. Previous studies described enhancement of agonist-induced Rho GTPase signaling and endothelial cell (EC) permeability in EC cultures exposed to pathologically relevant cyclic stretch (CS) magnitudes. This study examined a role of pathologic CS in modulation of pulmonary EC permeability caused by IL-6, a cytokine increased in sepsis and acting in a Rho-independent manner. IL-6 increased EC permeability, which was associated with activation of Jak/signal transducers and activators of transcription, p38 MAP kinase, and NF-B signaling and was augmented by EC exposure to 18% CS. Rho kinase inhibitor Y-27632 suppressed the synergistic effect of 18% CS on IL-6-induced EC monolayer disruption but did not alter the IL-6 effects on static EC culture. 18% CS also increased IL-6-induced ICAM-1 expression by pulmonary EC and neutrophil adhesion, which was attenuated by Y-27632. Intratracheal IL-6 administration in C57BL/6J mice increased protein content and cell count in bronchoalveolar lavage fluid. These changes were augmented by high tidal volume mechanical ventilation (HTV; 30 ml/kg, 4 h). Intravenous injection of Y-27632 suppressed IL6/HTV-induced lung injury. In conclusion, this study proposes a novel mechanism contributing to two-hit model of ALI: in addition to synergistic effects on Rho-dependent endothelial hyper-permeability triggered by thrombin, TNF␣, LPS, or other agonists, ventilator-induced lung injury-relevant CS may also exacerbate Rho-independent mechanisms of EC permeability induced by other inflammatory mediators such as IL-6 via mechanisms involving Rho activity. cyclic stretch; actin; interleukin-6; vascular permeability; endothelium VENTILATOR SUPPORT IS AN INDISPENSABLE treatment for critically ill patients. However, suboptimal regimen of mechanical ventilation leading to ventilator-induced lung injury (VILI), multiorgan dysfunction, and high rates of morbidity and mortality remain one of the most important problems in the management of patients with preexisting respiratory complications in the intensive care unit (31, 34).Pathologic mechanical forces leading to VILI trigger several signaling mechanisms including activation of signaling kinases, ion channels, small GTPases, second messengers, inflammatory signaling, and gene expression (14,16,39). Increased vascular endothelial permeability (2), inflammatory cytokine production (41), and apoptosis (18) induced by pathological mechanical stimulation causes alveolar flooding, leukocyte infiltration, and hypoxemia leadi...

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“…MCP-1 and to a lesser degree IL-6 are reduced in the airspace of obese animals with lung injury at 24 hours ( Figure E9). It is unclear whether this occurrence reflects a downstream effect of attenuated neutrophil recruitment (because neutrophils are an important source of IL-6 and MCP-1 release after lung injury [39]) or an evolving defect in the monocyte/macrophage or pulmonary epithelial response during the course of lung injury. In the case of IL-6, this decrease in alveolar cytokine release appears to mirror the defect seen in systemic cytokine response.…”

Section: Discussionmentioning

confidence: 99%

Obesity Is Associated with Neutrophil Dysfunction and Attenuation of Murine Acute Lung Injury

Kordonowy

Burg²,

Lenox³

et al. 2012

Am J Respir Cell Mol Biol

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Although obesity is implicated in numerous health complications leading to increased mortality, the relationship between obesity and outcomes for critically ill patients appears paradoxical. Recent studies have reported better outcomes and lower levels of inflammatory cytokines in obese patients with acute lung injury (ALI)/acute respiratory distress syndrome, suggesting that obesity may ameliorate the effects of this disease. We investigated the effects of obesity in leptin-resistant db/db obese and diet-induced obese mice using an inhaled LPS model of ALI. Obesity-associated effects on neutrophil chemoattractant response were examined in bone marrow neutrophils using chemotaxis and adoptive transfer; neutrophil surface levels of chemokine receptor CXCR2 were determined by flow cytometry. Airspace neutrophilia, capillary leak, and plasma IL-6 were all decreased in obese relative to lean mice in established lung injury (24 h). No difference in airspace inflammatory cytokine levels was found between obese and lean mice in both obesity models during the early phase of neutrophil recruitment (2-6 h), but early airspace neutrophilia was reduced in db/db obese mice. Neutrophils from uninjured obese mice demonstrated diminished chemotaxis to the chemokine keratinocyte cytokine compared with lean control mice, and adoptive transfer of obese mouse neutrophils into injured lean mice revealed a defect in airspace migration of these cells. Possibly contributing to this defect, neutrophil CXCR2 expression was significantly lower in obese db/db mice, and a similar but nonsignificant decrease was seen in diet-induced obese mice. ALI is attenuated in obese mice, and this blunted response is in part attributable to an obesity-associated abnormal neutrophil chemoattractant response.Keywords: adult respiratory distress syndrome; chemotaxis; cytokines; innate immunity Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by persistent, uncontrolled pulmonary inflammation that occurs in response to a wide range of insults, including pneumonia, sepsis, and trauma (1, 2). Alveolar recruitment of neutrophils is thought to be a central factor in the onset and progression of this syndrome (3, 4), and increases in airspace neutrophilia and plasma neutrophilic cytokine levels, including TNF-a, IL-1b, IL-6, and IL-8, are associated with increased morbidity and mortality from this disease (4-6). It is increasingly recognized that ALI pathogenesis and outcome are strongly influenced by host factors, including genetic polymorphisms and comorbid conditions (1, 2). Preliminary clinical evidence suggests that obesity may have an ameliorative effect on ALI outcome (7). Although ambiguity exists in smaller studies (8, 9), recent large cohort studies from our group and others, as well as several metaanalyses, have shown a reduction in mortality with rising body mass index in ALI and critical illness in general (7,(10)(11)(12)(13)(14)(15)(16). Such an association, though tentative, is surprising because obesity...

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Neutrophil-Derived IL-6 Limits Alveolar Barrier Disruption in Experimental Ventilator-Induced Lung Injury

Cited by 50 publications

References 27 publications

Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice

Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice

Stimulation of Rho signaling by pathologic mechanical stretch is a “second hit” to Rho-independent lung injury induced by IL-6

Obesity Is Associated with Neutrophil Dysfunction and Attenuation of Murine Acute Lung Injury

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