NEUTROPHILIC INFLAMMATION IN THE LUNG IMPROVES INSULIN SENSITIVITY: A MECHANISTIC STUDY IN A MOUSE MODEL OF METABOLIC SYNDROME

DELLA VEDOVA MC; MUÑOZ MD ; GARCIA S ; SANTILLAN LD; CASTRO CM ; FORNES MW.; SIEWERT SE ; GOMEZ MEJIBA SE; GOMEZ NN; RAMIREZ DC

Mendoza

Congreso; Reunion anual de la sociedad de biología de cuyo; 2016

A130NEUTROPHILIC INFLAMMATION IN THE LUNG IMPROVES INSULIN SENSITIVITY: A MECHANISTIC STUDY IN A MOUSE MODEL OF METABOLIC SYNDROME1Della Vedova, MC, 1Muñoz MD, 1Garcia S, 1Santillan LD, 3Castro CM, 3Fornes M, 1Siewert SE, 1Gomez Mejiba SE, 2Gomez NN, 1Ramirez DC1Lab of Experimental & Translational Medicine & Lab. of Experimental Therapeutics-CCT-San Luis-UNSL-CONICET. 2Lab. de Morfofisiología, IMIBIO-SL. 3CCT-Mendoza-UNCuyo. E-mail: ramirezlabimibiosl@ymail.comNeutrophilic inflammation (NI) is a poorly known process occurring in the lung of obese subjects exposed to indoor airborne pollutants that may worsen obesity-associated metabolic abnormalities, including insulin resistance (IR). Indeed, obese patients exposed to indoor-airborne pollutants show worse IR than those unexposed, however the mechanisms for this disparity are partially known. Bacterial lipopolysaccharide (LPS) is a stressor that when administrated by intratracheal instillation (ITI) causes NI in the lung. At sites of NI, myeloperoxidase (MPO) oxidizes chloride anions to hypochloroses acid/hypochlorite (HOCl/OCl), which can damage the lung, increase systemic oxidative stress/inflammation and thus worsen IR. Hydrazide 4-aminobenzoic acid (ABAH) is a fairly-specific inhibitor of MPO. Taurine is a non-cell-permeable scavenger of HOCl. Herein we hypothesized that inhibition of oxidative processes mediated by MPO in the lung can improve insulin sensitivity in an animal model of metabolic syndrome (MS). To test this hypothesis we used male B6 mice which were fed for 16 weeks a high-chicken-fat diet and fructose (MS) and a low-fat diet and tap-water (control). During the last week of diet and on a daily basis both groups of mice were ITI with either PBS (vehicle), ABAH (10 μmol/mouse) or taurine (5nmol/mouse). The last day of treatment animals were ITI with 2.5 μg LPS/mouse or PBS alone; and 6 h later an intraperitoneal glucose tolerance test was performed. A total of 6 groups, for both control and obese mice, were compared (PBS, LPS, ABAH, ABAH+LPS, Tau and Tau+LPS). Compared to control, LPS treatment to obese mice increased lung MPO activity, chlorotyrosine, nitrotyrosine and TNF-α; but reduced insulin sensitivity. These differences were abrogated when animals were pre-treated with either ABAH or taurine. We conclude that MPO-driven oxidative modifications in the lung of obese animals responsible for worsening IR and thus NI may provide a therapeutic target to reduce IR in obese subjects exposed to airborne pollutants.