**4.2 Inflammation**

Systemic inflammation is a common bound between COPD and DM. Both conditions are a proinflammatory state characterized by transcription and expression of hypoxia-induced factor 1 (HIF-1) and increased levels of serum inflammatory cytokines such as C-reactive protein (CRP), interleukin (IL) 1, IL-6 and tumor necrosis factor α (TNF-α) (Archer & Baker 2009). C-reactive protein (CRP) and the nuclear factor NF-κβ pathway are important mediators of the inflammatory response in this context (McNicholas, 2009).

CRP is a type I phase protein with the ability to bind the bacteria surface facilitating the fixation of complement that mediates bacterial killing and/or phagocytosis. CRP stimulates further cytokine production mainly through macrophages activation. TNF-α, IL-1 and IL-6 stimulate CRP synthesis by inducing its hepatic gene expression. NF-κβ is the master regulator of TNF-α, IL-8 and other cytokines transcription and synthesis. TNF-α and other cytokines are produced by monocytes and leukocytes and are enhanced by hypoxia in vitro studies (Takabatake et al., 2000 in Sevenoaks & Stockley, 2006).

TNF-α pathway is related with the deterioration of accessory muscles involved in ventilation. TNF-α induces loss of fat-free mass in COPD patients with subsequent loss of skeletal muscle function. Muscle wasting is also directly mediated by nuclear factor-κβ (NFκβ) that inhibits the MyoD gene expression. MyoD regulates myofibril synthesis and repairs. Secondly, TNF-α interaction with its receptor can activate muscle and other cellular apoptosis. Reduced IGF-1 and testosterone levels are also adjuvant factors leading to muscle wasting (Sevenoaks & Stockley, 2006).

CRP is a marker of COPD exacerbations and elevated pulmonary pressure in the stable disease (Zamarrón et al., 2008). If we look at the intermittent side of the obstructive disease, CRP is not identified as a prognostic marker of SAHS after adjustment for BMI. TNF-α pathway is related with muscle wasting and pulmonary hypertension commonly developed in COPD disease. NF-κβ and HIF-1 pathways are closely related and may have a differential role in chronic and intermittent hypoxia. Indeed, HIF-1 seems to have a predominant role in COPD, while NF-κβ pathways may predominate in the intermittent hypoxia of SAHS. TNFα levels can be predicted by the oxygen desaturation index in SAHS. Its levels are increased with independence of obesity (McNicholas, 2009). The prognostic value of these markers in overlap syndrome is unknown.
