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Promoting Neutrophil Apoptosis to Treat Acute Lung Injury
- Source :
- American Journal of Respiratory and Critical Care Medicine
- Publication Year :
- 2019
- Publisher :
- American Thoracic Society, 2019.
-
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 (hypoxia-inducible factor-1α)-mediated neutrophil adaptation, resulting in resolution of lung injury. Methods: Neutrophil activation of IL4Ra (IL-4 receptor α) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4. Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α–dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra–deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis. Conclusions: We describe an important interaction whereby IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury.
- Subjects :
- Pulmonary and Respiratory Medicine
Cell Survival
Neutrophils
Acute Lung Injury
Neutrophil apoptosis
Apoptosis
Receptors, Cell Surface
Lung injury
Critical Care and Intensive Care Medicine
Mice
Correspondence
Animals
Humans
Medicine
Mice, Knockout
Respiratory Distress Syndrome
hypoxia-inducible factor-1α
hypoxia
business.industry
IL-4
neutrophil
Interleukin-4 Receptor alpha Subunit
Original Articles
acute respiratory distress syndrome
Hypoxia-Inducible Factor 1, alpha Subunit
Cell Hypoxia
STAT Transcription Factors
Gene Expression Regulation
Cancer research
Interleukin-4
Signal transduction
business
Interstitial Lung Disease/Critical Care
Signal Transduction
Subjects
Details
- ISSN :
- 15354970 and 1073449X
- Volume :
- 200
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory and Critical Care Medicine
- Accession number :
- edsair.doi.dedup.....07445cf0804be64e13274c7e59ac7dfd