TARGETING 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 M; SIEWERT S; GOMEZ MEJIBA SE; GOMEZ NN; RAMIREZ DC

MZA

Congreso; SBC; 2016

Neutrophilicinflammation (NI) is a poorly known process occurring in the lung of obesesubjects exposed to indoor airborne pollutants that may worsenobesity-associated metabolic abnormalities, including insulin resistance (IR).Indeed, obese patients exposed to indoor-airborne pollutants show worse IR thanthose unexposed, however the mechanisms for this disparity are partially known.Bacterial lipopolysaccharide (LPS) is a stressor that when administrated byintratracheal instillation (ITI) causes NI in the lung. At sites of NI,myeloperoxidase (MPO) oxidizes chloride anions to hypochlorous acid/hypochlorite(HOCl/OCl-),which can damage the lung, increase systemic oxidative stress/inflammation andthus worsen IR. Hydrazide 4-aminobenzoic acid (ABAH) is a fairly-specificinhibitor of MPO. Taurine is a non-cell-permeable scavenger of HOCl. Herein wehypothesized that inhibition of oxidative processes mediated by MPO in the obeselung 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 ahigh-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 witheither PBS (vehicle), ABAH (10 µmol/mouse) or taurine (5nmol/mouse). The lastday-of-treatment animals were ITI with 2.5 µg LPS/mouse or PBS alone; and 6 hlater an intraperitoneal glucose tolerance test was performed. A total of 6groups, for both control and obese mice, were compared (PBS, LPS, ABAH,ABAH+LPS, Tau and Tau+LPS). Compared to control, LPS treatment to obese miceincreased more lung MPO activity, chlorotyrosine, nitrotyrosine, TNF-α; but reducedinsulin sensitivity. These differences were abrogated when animals werepre-treated with either ABAH or taurine. We conclude that MPO-driven oxidativemodifications in the lung of obese animals are responsible for worsening IR and,thus NI may provide a therapeutic target to reduce IR in obese subjects exposedto indoor-airborne pollutants. Supportedby PROICO 2-3214 & PICT-2014-3369 (to DCR), PROICO 10-0414 (To SEGM) andPIP2015-2017-112215-0100603CO (To DCR, SEA & SEGM).