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

Environ Health Perspect. 2019 May;127(5):57009. doi: 10.1289/EHP4591.


Background: 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.

Objective: 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).

Methods: [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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Air Pollutants / toxicity*
  • Animals
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Glucose / physiology*
  • Homeostasis*
  • I-kappa B Kinase / deficiency*
  • Lung / drug effects
  • Male
  • Mice
  • Mice, Transgenic
  • Particulate Matter / toxicity*
  • Vehicle Emissions / toxicity*


  • Air Pollutants
  • Particulate Matter
  • Vehicle Emissions
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Glucose