Fatty diabetic lung: functional impairment in a model of metabolic syndrome

Abstract

The Zucker diabetic fatty (ZDF fa/fa) rat with genetic leptin insensitivity develops obesity and Type 2 diabetes mellitus (T2DM) with age accompanied by hyperplastic changes in the distal lung (Am J Physiol Lung Cell Mol Physiol 298: L392-L403, 2010). To determine the functional consequences of structural changes, we developed a rebreathing (RB) technique to simultaneously measure lung volume, pulmonary blood flow, lung diffusing capacity (Dl(CO)), membrane diffusing capacity (Dm(CO)), pulmonary capillary blood volume (Vc), and septal tissue volume in anesthetized tracheostomized male ZDF fa/fa and matched lean (+/+) control animals at 4, 8, and 12 mo of age. Results obtained by RB technique were compared with that measured by a single-breath (SB) technique and to that expected in a wide range of species. In fa/fa animals compared with +/+, lung volumes and compliance were 13-35% lower at different ages, and the normal age-related increase in lung compliance was no longer evident. Mean pulmonary blood flow declined with age in fa/fa but not in +/+ animals. Dl(CO) measured at a given pulmonary blood flow was 20-43% lower at different ages due to reductions in both Dm(CO) and Vc. Septal tissue volume was also reduced in older fa/fa rats. We conclude that obese rats with T2DM develop significant restrictive pulmonary defects with diffusion impairment in a pattern similar to that previously reported in obese human subjects with T2DM. Functional impairment became exaggerated with age and duration of T2DM. In both fa/fa and +/+ animals, Dl(CO) measured by RB was systematically higher than by SB technique whereas lung volume was similar, a finding consistent with heterogeneous distribution of ventilation in the rat lung.

Alveolar–capillary adaptation to chronic hypoxia in the fatty lung

“…All animal procedures were performed within a span of 6 months by the same personnel using the same methods. Postmortem tissue analysis was first completed in the normoxia groups (+/+ and fa/fa); these results (lung function and morphometry) have been published (Foster et al, 2010, Yilmaz et al, 2010). Due to personnel constraints and other laboratory priorities, data analysis of hypoxia-exposed groups (+/+ and fa/fa) was completed later and the results reported here.…”

“…As described previously (Yilmaz et al, 2010), the tracheal cannula was attached via a manifold to the ventilator, a 10–20 mL glass syringe, and 2 three-way computer-controlled solenoid valves (GH3315, Hans Rudolph, Kansas City, MO). Total apparatus dead-space was 0.5 mL.…”

“…To characterize the effects of lipotoxicity on alveolar-capillary structure and function during hypoxia challenge, we utilized the Zucker diabetic fatty (ZDF) rat model (Yilmaz et al, 2010, Foster et al, 2010), which originated in outbred Zucker fatty ( fa/fa ) rats carrying the fa mutation, an amino acid substitution in the extracellular domain of the leptin receptor that renders the animal insensitive to leptin, leading to hyperphagia, diet-induced obesity, extra-adipocyte fat infiltration, systemic pro-inflammatory stress, end-organ damage and a shortened life span (Unger and Zhou, 2001, Unger and Scherer, 2010). The type-2 diabetic trait develops in an inbred substrain of obese fa/fa males [ZDF/Drt- fa ] receiving at least 6% dietary fat; hyperglycemia develops by age ~12 weeks as insulin production and peripheral insulin sensitivity decline (Shimabukuro et al, 1997, Shimabukuro et al, 1998).…”

Pulmonary Hemodynamics

“…Indeed, estimates of pulmonary capillary blood volume have repeatedly been made by the method that quantifies the overall diffusing capacity of the alveolar capillary membrane by the carbon monoxide/oxygen method (Roughton, 1945;Roughton and Forster, 1957). The use of this method in humans has indicated the capillary blood volume to be about 100 cc (Lewis et al, 1958;Bates et al, 1960), about 48 cc in the dog (Wanner et al, 1978), and about 0.77 ml in rats (Yilmaz et al, 2010). Importantly, there have been suggestions that the capillary blood volume determined by this method may be significantly underestimated and that the true volume in humans may be as high as 150e213 cc (Gehr et al, 1978;Cumming et al, 1969) and in excess of 100 cc in the dog (Smiseth et al, 1988;Wanner et al, 1978;Zarbock et al, 2009).…”

“…This vision neglects the possible contribution of gravity and the resulting development of Starling, rather than Ohmic, resistance within the different zones of the lung (Rock et al, 1985;Brower et al, 1986). Second, these analogue elements are not equal or equally distributed, and can change as a result of disease-induced anatomical changes, or with changes in baseline tone and reactivity of the vasculature itself (Horsfield and Gordon, 1981;Yilmaz et al, 2010;West et al, 1975;Wagner et al, 1979). As a result, future analogue models should include, in some fashion, variable resistance, capacitance, and impedance elements to be more realistic.…”