资源环境科技发展态势分析平台

Background: Pulmonary inflammation is believed to be central to the pathogenesis due to exposure to fine particulate matter with aerodynamic diameter <= 2.5 mu m (PM2.5). This central role, however, has not yet been systemically examined.

Objective: In the present study, we exploited a lung epithelial cell-specific inhibitor kappa B 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).

Methods: SFTPC-rtTA(+/-)tetO-cre(+/-)IKK2(flox/flox) (lung epithelial cell-specific IKK2 knockout, KO) and SFTPC-rtTA(+/-)tetO-cre(+/-)IKK2(flox/flox) (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.

Results: 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.

Discussion: 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.