Related Experiment Videos
From the Cover: Lung-Specific Overexpression of Constitutively Active IKK2 Induces Pulmonary and Systemic
Minjie Chen1,2, Huifen Zhou1,3, Yanyi Xu2
1Cardiology Division, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201.
Abstract:
The lung is constantly exposed to ambient pollutants such as ambient fine particulate matter (PM2.5), making it one of the most frequent locations of inflammation in the body. Given the establishment of crucial role of inflammation in the pathogenesis of cardiometabolic diseases, pulmonary inflammation is thus widely believed to be an important risk factor for cardiometabolic diseases. However, the causality between them has not yet been well established. To determine if pulmonary inflammation is sufficient to cause adverse cardiometabolic effects, SFTPC-rtTA+/-tetO-cre+/-pROSA-inhibitor κB kinase 2(IKK2)ca+/- (LungIKK2ca) and littermate SFTPC-rtTA+/-tetO-cre-/-pROSA-IKK2ca+/- wildtype (WT) mice were fed with doxycycline diet to induce constitutively active Ikk2 (Ikk2ca) overexpression in the lung and their pulmonary, systemic, adipose, and hypothalamic inflammations, vascular function, and glucose homeostasis were assessed. Feeding with doxycycline diet resulted in IKK2ca overexpression in the lungs of LungIKK2ca but not WT mice. This induction of IKK2ca was accompanied by marked pulmonary inflammation as evidenced by significant increases in bronchoalveolar lavage fluid leukocytes, pulmonary macrophage infiltration, and pulmonary mRNA expression of tumor necrosis factor α (Tnfα) and interleukin-6 (Il-6). This pulmonary inflammation due to lung-specific overexpression of IKK2ca was sufficient to increase circulating TNFα and IL-6 levels, adipose expression of Tnfα and Il-6 mRNA, aortic endothelial dysfunction, and systemic insulin resistance. Unexpectedly, no significant alteration in hypothalamic expression of Tnfα and Il-6 mRNA and glucose intolerance were observed in these mice. Pulmonary inflammation is sufficient to induce systemic inflammation, endothelial dysfunction, and insulin resistance, but not hypothalamic inflammation and glucose intolerance.
Insights
Pulmonary inflammation from lung-specific overexpression of inhibitor κB kinase 2 (IKK2) caused systemic inflammation and insulin resistance. However, it did not lead to hypothalamic inflammation or glucose intolerance in mice.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cardiovascular Science
Background:
- The lungs are frequently inflamed due to pollutant exposure, and pulmonary inflammation is linked to cardiometabolic diseases.
- The causal relationship between pulmonary inflammation and cardiometabolic diseases requires further investigation.
- Understanding this link is crucial for developing targeted therapies.
Purpose of the Study:
- To determine if lung inflammation is sufficient to cause adverse cardiometabolic effects.
- To investigate the impact of induced pulmonary inflammation on systemic and organ-specific inflammation, vascular function, and glucose homeostasis.
Main Methods:
- Mice with lung-specific overexpression of constitutively active inhibitor κB kinase 2 (LungIKK2ca) and wildtype (WT) littermates were used.
- Doxycycline was administered to induce IKK2ca overexpression in the lungs of LungIKK2ca mice.
- Pulmonary, systemic, adipose, and hypothalamic inflammation, vascular function, and glucose homeostasis were assessed.
Main Results:
- Lung-specific IKK2ca overexpression successfully induced pulmonary inflammation, marked by increased leukocytes, macrophage infiltration, and pro-inflammatory cytokine mRNA.
- Induced pulmonary inflammation led to elevated circulating TNFα and IL-6 levels.
- Systemic effects included increased adipose inflammation, aortic endothelial dysfunction, and systemic insulin resistance.
Conclusions:
- Lung inflammation alone is sufficient to induce systemic inflammation, endothelial dysfunction, and insulin resistance.
- Pulmonary inflammation did not significantly alter hypothalamic inflammation or cause glucose intolerance in this model.
- These findings highlight the systemic impact of lung inflammation on cardiometabolic health.