Lung volume dependence of respiratory function in rodent models of diabetes mellitus

Abstract

Background Diabetes mellitus causes the deterioration of smooth muscle cells and interstitial matrix proteins, including collagen. Collagen and smooth muscle cells are abundant in the lungs, but the effect of diabetes on airway function and viscoelastic respiratory tissue mechanics has not been characterized. This study investigated the impact of diabetes on respiratory function, bronchial responsiveness, and gas exchange parameters. Methods Rats were allocated randomly to three groups: a model of type 1 diabetes that received a high dose of streptozotocin (DM1, n = 13); a model of type 2 diabetes that received a low dose of streptozotocin with a high-fat diet (DM2, n = 14); and a control group with no treatment (C, n = 14). Forced oscillations were applied to assess airway resistance (Raw), respiratory tissue damping (G), and elastance (H). The arterial partial pressure of oxygen to the inspired oxygen fraction (PaO2/FiO2) and intrapulmonary shunt fraction (Qs/Qt) were determined from blood gas samples at positive end-expiratory pressures (PEEPs) of 0, 3, and 6 cmH2O. Lung responsiveness to methacholine was also assessed. Collagen fibers in lung tissue were quantified by histology. Results The rats in groups DM1 and DM2 exhibited elevated Raw, G, H, and Qs/Qt, compromised PaO2/FiO2, and diminished airway responsiveness. The severity of adverse tissue mechanical change correlated with excessive lung collagen expression. Increased PEEP normalized the respiratory mechanics, but the gas exchange abnormalities remained. Conclusions These findings indicate that diabetes reduces airway and lung tissue viscoelasticity, resulting in alveolar collapsibility that can be compensated by increasing PEEP. Diabetes also induces persistent alveolo-capillary dysfunction and abnormal adaptation ability of the airways to exogenous constrictor stimuli.

Pulmonary impairment in type 2 diabetic rats and its improvement by exercise

“…Hysteresis is calculated as the ratio G / H , and its value increases because of a proportionally greater increase in G than in H as the lung becomes mechanically more heterogeneous 40 (Figure 3D). Changes in lung function have been documented both in experimental models of diabetes 16 and humans 6,34 . Moreover, our results may suggest the frequent occurrence of compromised lung function in diabetes because it was observed in MD and in the face of slow hyperglycaemic evolution.…”

“…G and H may vary because of modification in the rheological properties of lung parenchyma 37 . These changes are initiated by the biochemical and inflammatory cascade triggered by hyperglycaemia, which leads to lung tissue modifications, including remodelling of the extracellular matrix 16,37 . In fact, a higher G indicates a heterogeneous narrowing of distal airways and changes in the intrinsic rheological properties of the parenchyma, 38 while the increment in H depends largely on alveolar collapse 39 .…”

“…STZ model disclosed lung impairment, evidenced by increased redox imbalance, 13,14 alveolar collapse, septal thickening, cellular infiltration and parenchymal haemorrhage 15 . Recently, detrimental changes in airway function, viscoelastic tissue mechanics and collagen expression have been reported in the lungs of T1D and T2D rats 16 …”

Association of Pulmonary Function Decline over Time with Longitudinal Change of Glycated Hemoglobin in Participants without Diabetes Mellitus

“…The mechanism of pulmonary dysfunction in hyperglycemic status and overt DM was multifactorial [35], including insulin resistance, oxidative stress, elastic fibers remodeling, excessive pulmonary collagens expression, and smooth muscle dysfunction [36][37][38][39]. Singh et al showed hyperinsulinemia-induced activation of β-catenin mediated pulmonary fibrosis and epithelial-mesenchymal transition in mice and human airway smooth muscle cells [36].…”

“…Clemmer et al showed hyperglycemia was associated with increased pulmonary vascular permeability via the superoxide pathway in obese rats [37]. Südy et al also found that increased pulmonary tissue viscoelasticity was associated with the alveolar collapse in diabetic rats [38]. The hyperglycemic effects on the airway and alveolar regions could result in an increase in pulmonary elastic fiber remodeling, and therefore, reduce pulmonary volume [36][37][38][39][40].…”