key: cord-0999824-0t5lr4z9 authors: Moin, Abu Saleh Md; Sathyapalan, Thozhukat; Atkin, Stephen L.; Butler, Alexandra E. title: Pro-fibrotic M2 macrophage markers may increase the risk for COVID19 in type 2 diabetes with obesity()() date: 2020-09-16 journal: Metabolism DOI: 10.1016/j.metabol.2020.154374 sha: a7d9753ebba0ccf0474ebbad8687a9e873f445fa doc_id: 999824 cord_uid: 0t5lr4z9 nan rate Modified Aptamer (SOMA)-scan plasma protein measurement [7] was used to determine LPS-binding protein (LBP), TGFβ-1, PDGF-β, MMP7 and MMP9 protein concentration, expressed as relative fluorescent units (RFU). Statistical analysis was performed using the Student's t-test (GraphPad Prism 8.0, San Diego, CA). LPS-binding (LBP) protein was reduced in plasma (85,311.3 ± 1453.1 vs 91,746.9 ± 3047.9 RFU, OT2D vs control, p < 0.05). Plasma LBP was also reduced in obese versus non-obese subjects regardless of diabetic status (84,343. 5 We report here that LPS-related markers were associated with activated lung alveolar M2 macrophages in OT2D, with a reduction in plasma LBP as a surrogate marker of circulatory LPS elevation. Previously increased LBP levels were reported in obesity [8, 9] , a discrepancy compared to our observations that might be due to inclusion of obese subjects whom were smokers and alcoholic in those studies. LBP was increased in the bronchoalveolar lavage fluid (BALF) of smokers [10] . Serum levels of LBP are also increased in heavy drinkers, probably reflecting high LPS exposure due to alcohol-induced damage of the gastrointestinal barrier [11, 12] . By contrast, in our study none of the OT2D subjects were smokers or consumed alcohol, as those were exclusion criteria. Moreover, LBP, the serum glycoprotein, plays a concentrationdependent dual role in determining LPS-induced macrophage activation; low concentrations of LBP enhance the LPS-induced activation of mononuclear cells (MNC), whereas the acute-phase rise in LBP concentration inhibits LPS-induced cellular stimulation [13] . Furthermore, LBP is bound and internalized by host cells and colocalizes with LPS in the cytoplasm [14] . Therefore, the significantly lower LBP levels reflect the elevated LPS levels in OT2D subjects in our study. The elevated TGF-β1 shown here may predispose to alveolar pre-fibrosis with their collapse following SARS-CoV-2 infection. TGF-β is detected in lung bronchoalveolar lavage fluid of 90% of patients with ARDS, major cellular sources of TGF-β in pulmonary fibrosis being alveolar macrophages and metaplastic type II alveolar epithelial cells. Activation of TGF-β1 is affected by MMP9 that was elevated here in OT2D, contributing to enhancement of the pool of active TGF-β1. MMP9 also weakens the airway epithelial barrier function by altering transepithelial electrical conductance and epithelial permeability to macromolecules [15] . MMP7, also elevated here, is increased in ARDS and associated with idiopathic pulmonary fibrosis (IPF), whilst PDGFβ, again elevated here, contributes to fibrosis development with TGF-β in ARDS. Elevated plasma levels of TGF-β1, PDGF-β, MMP7 and MMP9 determined early in the course of COVID19 infection in a patient with OT2D may indicate potential risk for more severe disease. The strengths of this study include the inclusion of a group of OT2D subjects who were relatively treatment naïve and not on poly-pharmacy, and an age-matched healthy control group together with statehttps://doi.org/10.1016/j.metabol.2020.154374 0026-0495/© 2020 Elsevier Inc. All rights reserved. of-the-art measurement of plasma proteins by SOMA-scan. Limitations include the relatively small study subject numbers and that all participants were Caucasian, so the results may not be generalizable to other ethnic groups. Moreover, it is also possible that, apart from alveolar macrophages, other cellular sources, for example lung epithelial cells [16] , arterial smooth muscle cells [17] , epithelial cells of glandular tissues like prostate [18] or bile duct epithelia [19] , might contribute to LPS-induced elevated plasma levels of those pro-fibrotic markers. In conclusion, in OT2D the lung epithelial barrier integrity is likely destabilized in response to fibroproliferative activity of elevated TGF-β1, PDGF-β, MMP7 or MMP9 derived from lung alveolar macrophages, increasing vulnerability to inhaled pathogens. This might lead to irreversible structural alterations and tissue stiffening in the lungs of OT2D patients even prior to SARS-COV-2 infection and thereby make these patients more vulnerable to COVID19-related infection with severe disease. The Yorkshire and Humber Research Ethics Committee approved this study. All patients gave written informed consent. All authors gave their consent for publication. All the data for this study will be made available upon reasonable request to the corresponding author. No funding was received to perform this study. Commentary: COVID-19 and obesity: exploring biologic vulnerabilities, structural disparities, and weight stigma Pulmonary postmortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages The chemokine system in diverse forms of macrophage activation and polarization A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18 Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity Lipopolysaccharide-binding protein and CD14 are increased in the bronchoalveolar lavage fluid of smokers Concentrations of lipopolysaccharide-binding protein, bactericidal/permeability-increasing protein, soluble CD14 and plasma lipids in relation to endotoxaemia in patients with alcoholic liver disease Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease Dual role of lipopolysaccharide (LPS)-binding protein in neutralization of LPS and enhancement of LPS-induced activation of mononuclear cells Lipopolysaccharide-binding protein is bound and internalized by host cells and colocalizes with LPS in the cytoplasm: implications for a role of LBP in intracellular LPS-signaling MMP9 modulates tight junction integrity and cell viability in human airway epithelia Regulation of matrilysin expression in airway epithelial cells by Pseudomonas aeruginosa flagellin Lipopolysaccharide regulates MMP-9 expression through TLR4/NF-κB signaling in human arterial smooth muscle cells LPS/TLR4 signaling enhances TGF-β response through downregulating BAMBI during prostatic hyperplasia Lipopolysaccharide enhances transforming growth factor β1-induced platelet-derived growth factor-B expression in bile duct epithelial cells No authors have any conflict of interest or competing interests to declare.