Increased Adipose Tissue Expression of Proinflammatory CD40, MKK4 and JNK in Patients with Very Severe Chronic Obstructive Pulmonary Disease

Background: CD40, a transmembrane receptor of the tumor necrosis factor gene superfamily, is activated in response to cellular stress, including hypoxia, and orchestrates the process of inflammation via secondary messengers such as mitogen-activated protein kinase kinase 4 (MKK4) and c-Jun NH2-terminal kinases (JNK). Objectives: We hypothesized that CD40, MKK4 and JNK expression is increased in the adipose tissue of patients with very severe chronic obstructive pulmonary disease (COPD). Methods: In 20 patients with stable COPD, lung function was assessed using body plethysmography, and samples of subcutaneous adipose tissue were analyzed using real-time PCR. Body composition, including fat mass index (FMI), was assessed by bioelectrical impedance. Results: 12 patients in GOLD stage I–III (age 61.6 ± 8.6 years, 4 females, mean partial pressure of oxygen in arterial blood, PaO2, 9.38 ± 0.21 kPa) were compared to 8 patients in GOLD stage IV (age 62.6 ± 6.3 years, all male, mean PaO2 7.70 ± 0.37 kPa). Compared to patients in GOLD stage I–III, patients in GOLD stage IV had lower FMI (p = 0.004), being associated with significantly higher adipose tissue expression of CD40, MKK4 and JNK [ΔΔCt: 2.55 (1.99, 4.40) vs. 1.87 (1.63, 2.23), p = 0.013; 5.19 (3.13, 5.96) vs. 2.98 (2.82, 3.86), p = 0.002; 9.01 (5.12, 11.41) vs. 4.65 (4.42, 6.26), p = 0.001, respectively]. Log-transformed CD40, MKK4 and JNK expression was significantly inversely related to PaO2, respectively. Conclusions: Upregulation of proinflammatory CD40, MKK4 and JNK gene expression in adipose tissue in very severe COPD raises the possibility of a role of chronic systemic hypoxia in the pathogenesis of adipose tissue inflammation in COPD.

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