Glucose Homeostasis following Diesel Exhaust Particulate Matter Exposure in a Lung Epithelial Cell-Specific IKK2-Deficient Mouse Model

• Published in: Environmental health perspectives Vol. 127; no. 5; p. 57009
• Main Authors: Chen, Sufang, Chen, Minjie, Wei, Wei, Qiu, Lianglin, Zhang, Li, Cao, Qi, Ying, Zhekang
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences 01.05.2019; Environmental Health Perspectives
• Subjects: Air Pollutants - toxicity; Air pollution; AKT protein; Alveoli; Analysis; Animals; Bioindicators; Bronchus; Cytokines; Diabetes; Diesel; Diesel emissions; Diesel engines; Disease Models, Animal; EDTA; Enzyme inhibitors; Epithelial cells; Epithelial Cells - drug effects; Exposure; Glucose; Glucose - physiology; Glucose tolerance; Homeostasis; I-kappa B Kinase - deficiency; IKK2 protein; Immune system; Immunological tolerance; Inflammation; Inflammatory response; Insulin; Insulin receptor substrate 1; Insulin resistance; Kinases; Lung - drug effects; Lungs; Male; Medical equipment industry; Mice; Mice, Transgenic; Outdoor air quality; Particulate matter; Particulate Matter - toxicity; Particulates; Pathogenesis; Phosphorylation; Serine; Studies; Substrates; Type 2 diabetes; Vehicle Emissions - toxicity; United States; Maryland; China
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/EHP4591

Pulmonary inflammation is believed to be central to the pathogenesis due to exposure to fine particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]). This central role, however, has not yet been systemically examined. In the present study, we exploited a lung epithelial cell-specific inhibitor [Formula: see text] kinase 2 (IKK2) knockout mouse model to determine the role of pulmonary inflammation in the pathophysiology due to exposure to diesel exhaust particulate matter (DEP). [Formula: see text] (lung epithelial cell-specific IKK2 knockout, KO) and [Formula: see text] (wild-type, tgWT) mice were intratracheally instilled with either vehicle or DEP for 4 months, and their inflammatory response and glucose homeostasis were then assessed. In comparison with tgWT mice, lung epithelial cell-specific IKK2-deficient mice had fewer DEP exposure-induced bronchoalveolar lavage fluid immune cells and proinflammatory cytokines as well as fewer DEP exposure-induced circulating proinflammatory cytokines. Glucose and insulin tolerance tests revealed that lung epithelial cell-specific IKK2 deficiency resulted in markedly less DEP exposure-induced insulin resistance and greater glucose tolerance. Akt phosphorylation analyses of insulin-responsive tissues showed that DEP exposure primarily targeted hepatic insulin sensitivity. Lung epithelial cell-specific IKK2-deficient mice had significantly lower hepatic insulin resistance than tgWT mice had. Furthermore, this difference in insulin resistance was accompanied by consistent differences in hepatic insulin receptor substrate 1 serine phosphorylation and inflammatory marker expression. Our findings suggest that in a tissue-specific knockout mouse model, an IKK2-dependent pulmonary inflammatory response was essential for the development of abnormal glucose homeostasis due to exposure to DEP. https://doi.org/10.1289/EHP4591.