Concentrated Ambient PM2.5-Induced Inflammation and Endothelial Dysfunction in a Murine Model of Neural IKK2 Deficiency

BACKGROUND: Exposure to ambient fine particulate matter (PM 2:5 ) is associated with cardiovascular mortality, but underlying pathophysiologic mechanisms are not fully understood. Hypothalamic inflammation, characterized by the activation of Inhibitor kappaB kinase 2/Nuclear factor kappaB (IKK2=NF-jB) signaling pathway, may play an important role in the pathogenesis of cardiovascular diseases. We recently demonstrated that hypothalamic inflammation is increased in mice exposed to concentrated ambient PM 2:5 (CAP). OBJECTIVES: In the present study, we used a neuron-specific IKK2 knockout mouse model to examine the role of neural IKK2 expression and hypothalamic inflammation in the pathophysiologic effects of PM 2:5 . METHODS: We assessed inflammatory and vascular responses in Nestin-creIKK2 flox=flox (IKK2 Neu-KO ) and littermate Nestin-creIKK2 flox= + (control) mice after 4 mo of exposure to filtered air (FA) or CAP. RESULTS: CAP exposure was associated with significantly higher tumor necrosis factor-a TNFa and interleukin (IL)-6 mRNA in the hypothalamus of control mice, but not IKK2 Neu-KO mice. In addition, CAP exposure-induced increases in bronchoalveolar lavage fluid (BALF) leukocytes, pulmonary macrophage infiltration and IL-6 expression, plasma TNFa and IL-1b levels, adipose macrophage infiltration and IL-1b expression, and endothelial dysfunction were reduced or absent in IKK2 Neu-KO mice compared with controls. CONCLUSIONS: Our findings support a role of neural IKK2 in CAP exposure-induced local and systemic pro-inflammatory cytokine expression, pulmonary and adipose inflammation, and endothelial dysfunction, thus providing insight into pathophysiologic mechanisms that may mediate effects of PM 2:5 exposure.