Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here, we show that interleukin-11 (IL11) is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle–positive (ACTA2+), collagen-secreting myofibroblasts in an extracellular signal–regulated kinase (ERK)–dependent, posttranscriptional manner. In mice, fibroblast-specific transgenic expression or administration of murine IL-11 induces lung myofibroblasts and causes lung fibrosis. IL-11 receptor subunit alpha-1 (Il11ra1)–deleted mice, whose lung fibroblasts are unresponsive to profibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11–neutralizing antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti–IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice. These data prioritize IL-11 as a drug target for lung fibrosis and IPF.

BACKGROUND & AIMS: Noninvasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS: We developed a test to measure 13 proteins in blood (ANG1, ANG2,

Abstract:Idiopathic pulmonary fibrosis (IPF) remains a progressive disease despite best medical management. We previously identified IL-11 as a critical factor for cardiovascular fibrosis and examine here its role in pulmonary fibrosis. IL-11 is consistently upregulated in IPF genomic datasets, which we confirmed by histology. Pulmonary fibroblasts stimulated with IL-11 transform into invasive myofibroblasts whereas fibroblasts from Il11ra deleted mice did not respond to pro-fibrotic stimuli. In the mouse, injection of recombinant Il-11 or fibroblast-specific expression of Il-11 caused pulmonary fibrosis. We then generated a neutralising IL-11 binding antibody that blocks lung fibroblast activation across species. In a mouse model of IPF, anti-IL-11 therapy attenuated lung fibrosis and specifically blocked Erk activation. These data prioritise IL-11 as an accessible drug target in IPF. One Sentence Summary:Non-canonical IL-11 signalling is a central hallmark of idiopathic pulmonary fibrosis and represents a novel target for antibody therapies. Main Text:Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is characterised by epithelial injury and activation of invasive fibroblasts that deposit and remodel extracellular matrix (ECM) destroying tissue integrity (1, 2). Aging, genetic and environmental factors are known to trigger IPF but the underlying pathological mechanisms remain poorly characterised (2). Anti-inflammatory agents do not improve clinical outcomes (3-5), emphasizing the central role of fibroblast biology in IPF. Two anti-fibrotic drugs, nintedanib (6) and pirfenidone (7), are approved for the treatment of IPF but have notable toxicities (2) and despite best medical practice IPF remains a fatal disease and an unmet clinical need. Unfortunately recent clinical trials in IPF have not shown efficacy and new approaches based on a better understanding of disease biology are needed (8).Transforming growth factor-beta 1 (TGFβ1) is considered the principal pro-fibrotic cytokine and plays an important role in lung fibrosis (9), but TGFβ1-targeting therapies have marked side effects due to the pleiotropic roles of TGFβ1 in diverse cell types (8, 10). We recently screened for fibroblast-specific mediators of TGFβ1 activity in human cardiac fibroblasts and identified interleukin-11 (IL-11) as a crucial fibroblast-specific factor for cardiovascular fibrosis (11). In the lung there is conflicting literature for IL-11 that suggests it may either promote (12) or protect (13, 14) against lung damage, inflammation and/or fibrosis. Likely because of these discrepancies, the study of IL-11 biology in the lung has not progressed over the past decades. In recent genome wide studies IL-11 was found to be the most upregulated gene in fibroblasts from patients with IPF (15) but this chance observation was not explored further. Here we examined the hypothesis that IL-11 may be important for lung fibroblast activation and the pathobiology of IPF.. CC-BY-ND 4.0 International license It is made avai...

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Background: There is an increasing frequency of oncology and hematopoietic stem cell transplant (HSCT) patients seen in the intensive care unit and requiring extracorporeal membrane oxygenation (ECMO), however, prognosis of this population over time is unclear. Methods: MEDLINE, EMBASE, Cochrane and Web of Science were searched from earliest publication until April 10, 2020 for studies to determine the mortality trend over time in oncology and HSCT patients requiring ECMO. Primary outcome was hospital mortality. Random-effects meta-analysis model was used to obtain pooled estimates of mortality and 95% confidence intervals. A priori subgroup metanalysis compared adult versus pediatric, oncology versus HSCT, hematological malignancy versus solid tumor, allogeneic versus autologous HSCT, and veno-arterial versus veno-venous ECMO populations. Multivariable meta-regression was also performed for hospital mortality to account for year of study and HSCT population. Results: 17 eligible observational studies (n = 1109 patients) were included. Overall pooled hospital mortality was 72% (95% CI: 65, 78). In the subgroup analysis, only HSCT was associated with a higher hospital mortality compared to oncology subgroup [84% (95% CI: 70, 93) vs. 66% (95% CI: 56, 74); P = 0.021]. Meta-regression showed that HSCT was associated with increased mortality [adjusted odds ratio (aOR) 3.84 (95% CI 1.77, 8.31)], however, mortality improved with time [aOR 0.92 (95% CI: 0.85, 0.99) with each advancing year]. Conclusion: This study reports a high overall hospital mortality in oncology and HSCT patients on ECMO which improved over time. The presence of HSCT portends almost a 4-fold increased risk of mortality and this finding may need to be taken into consideration during patient selection for ECMO.