2019
DOI: 10.1164/rccm.201808-1599oc
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IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo

Abstract: Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood. Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1α (hyp… Show more

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Cited by 44 publications
(33 citation statements)
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“…This cytokine has not been previously linked to CAID, although studies in humans and animal models support a protective role for elevated IL4 in sepsis 15,16 and acute lung injury. 17 We demonstrated that manipulation of IL4 switched immune restoration-like phenotypes between survival and non-survival and suggests IL4 agonism may represent a potential immunerestorative target in AD/ACLF patients who develop increased circulatory inflammatory markers during hospitalization.…”
Section: Discussionmentioning
confidence: 84%
“…This cytokine has not been previously linked to CAID, although studies in humans and animal models support a protective role for elevated IL4 in sepsis 15,16 and acute lung injury. 17 We demonstrated that manipulation of IL4 switched immune restoration-like phenotypes between survival and non-survival and suggests IL4 agonism may represent a potential immunerestorative target in AD/ACLF patients who develop increased circulatory inflammatory markers during hospitalization.…”
Section: Discussionmentioning
confidence: 84%
“…Here, excessive neutrophil activation, including the degranulation of histotoxic proteins and pro-inflammatory cytokines, propagate diffuse host lung damage with high mortality [125]. In a murine model of hypoxia-induced acute lung injury, abrogation of hypoxic neutrophil survival by treatment with intra-tracheal IL-4 was able to promote resolution of inflammation and resulted in reduced bronchoalveolar lavage NE content, although the direct effect of IL-4 on degranulation was not assessed in this study [126]. Inhibition of glycolysis has also been shown to prevent neutrophil-driven tissue damage in murine acute lung injury [127].…”
Section: Hypoxia-enhanced Neutrophil Degranulation Can Damage Host Timentioning
confidence: 78%
“…IL-4 has been widely studied in relation to its effect on lymphoid cells, centrally involved in T helper cell differentiation, B cell class switch (52,53), as well as effects on nonimmune stromal cells (54). An emerging field related to IL-4R signaling in neutrophils is broadening the implications under conditions with increased IL-4 and IL-13 levels, such as allergic reactions and parasitic infections, but also related to therapeutic interventions affecting this pathway (55,56). For example, an interesting connection between the increased susceptibility to skin infections in patients with the TH2 centric disease atopic dermatitis and the suppression of neutrophil migration by IL-4R signaling has been proposed (29,34).…”
Section: Discussionmentioning
confidence: 99%