IL4Rα signaling abrogates hypoxic neutrophil survival and limits acute lung injury responses <i>in vivo</i>

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-1a (hypoxia-inducible factor-1a)mediated neutrophil adaptation, resulting in resolution of lung injury.  Methods: Neutrophil activation of IL4Ra (IL-4 receptor a) 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-1a-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 IL4Ra-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury

Validation of the ACE (Albumin, CRP and Endoscopy) Index in Acute Colitis:Analysis of the CONSTRUCT dataset

Background and Aims: In 2020 we reported the ACE Index in Acute Colitis which used biochemical and endoscopic parameters to predict steroid non-response on admission in patients with acute ulcerative colitis (UC). We aimed to validate the ACE Index in an independent cohort.Methods: The validation cohort comprised the patients screened as eligible for inclusion in the CONSTRUCT study, a prospective, randomised, placebo-controlled trial which compared the effectiveness of treatment with infliximab versus ciclosporin in patients admitted with acute UC. The CONSTRUCT cohort database was reviewed at The Edinburgh IBD Unit and the same biochemical and endoscopic variables and cut-off values as those in the derivation cohort were applied to the validation cohort.Results: In total, 800 patients were identified. 62.5% (55/88) of patients with a maximum ACE Index of 3 did not respond to IV steroids (positive predictive value (PPV) 62.5%, negative predictive value (NPV) 79.8%). Furthermore, 79.8% (158/198) of patients with an ACE Index of 0 responded to IV steroids (PPV 79.8%, NPV 62.5%). Receiver Operator Characteristic (ROC) curve analysis produced an Area Under the Curve (AUC) of 0.663 (p=&lt;0.001).Conclusions: We have now reported and externally validated the ACE Index in Acute Colitis in a combined cohort of over 1000 patients from across the United Kingdom. The ACE Index may be used in conjunction with clinical judgement to help identify patients admitted with active UC who are at high risk of not responding to IV steroids. Further studies are required to improve objectivity and accuracy of assessment.</p