410 - Neutrophils in the Obese Lung: A Mechanistic Study in a Mouse Model of Metabolic Syndrome

Abstract

The metabolic syndrome (MS) is a deadly metabolic abnormality-associated to obesity. The pulmonary microvasculature is a sink of circulating neutrophils; as well as this is highly sensitive to small changes in the systemic oxidative/inflammatory profile, as occur in chronic inflammatory diseases, such as obesity. Previously, we have characterized a MS-mouse model in which animals were fed for 16 weeks a 22% p/p chicken-fat rich diet and 10 % fructose in the drinking water. These animals show several features of MS including obesity, central adiposity, insulin resistance (IR), hypertension, dyslipidemia and streatohepatitis. Using this model we envisioned to test whether MS predisposes to pulmonary retention/activation of neutrophils and how it affects whole-body IR. To accomplish this goal we studied MS and control mice (B6 mice fed for 16 weeks with low-fat diet/tap water). MS mice had more IR than control mice. MS mice had also higher concentration of circulating inflammatory mediators than control mice. The lung tissue of MS mice was lighter and expressed more inflammation mediators (TNF-α; IL-6 and inducible nitric oxide) than the control lung. The lung of MS mice had more neutrophils (NIMP-14 + cells), myeloperoxidase (MPO) activity and chlorotyrosine than control mice. ICAM-1 expression in MS mice’s lung tissue was higher than control mice. In relation to control mice, intratracheal instillation (ITI) 2.5 ug lipopolysaccharide (LPS)/mouse to MS mice caused more retention/activation of neutrophils, ICAM-1 expression, MPO activity, chlorotyrosine, circulating inflammatory mediators and also worsened IR. These effects where damped by ITI of 5 nmol of 5,5-dimetil-1-pirrolina N-oxido/mouse. Our data suggest that retention/activation of neutrophils in the lung may be a potential therapeutic target to reduce IR and other complications of obesity. Supported by PROICO 2-3214 & PICT-2014-3369 (toDCR), PROICO 10-0414 (ToSEGM) and PIP2015-2017-112215-0100603CO (To DCR, SEA & SEGM).