**4.1 Hypoxia**

Hypoxemia and also hypercapnia, though in a less extent, are a stimulus for the hyperactivation of the sympathetic nervous system. In this setting, the activity of the sympathetic system is sustained in a non-resting anomalous way (Ashley et al., 2010; Heindl et al., 2001; Raupauch et al., 2008). Sustained hypoxia in COPD is an important central sympathetic system drive. A higher and long-lasting muscle sympathetic nerve activity (MSNA) is seen in COPD patients. Its direct consequence is a permanent vasoconstriction of the muscle vessels. Ashley et al. did not only show a sympathetic burst of multiple neurones, but they also graded the intensity of the response. The method used was the measurement of the firing probability and mean firing rates of single muscle vasoconstrictor

Chronic Obstructive Pulmonary Disease and Diabetes *Mellitus* 245

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

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

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

Now considering the cellular immune response, the leucocitary drive in COPD is a fountain of reactive oxygen species (ROS). The oxidative response advocates a protein, lipid and DNA damage within the cell. Oxidative stress influences NF-κβ cascade through

On the inverse loop, TNF-α stimulates ROS production. Indeed, an additional ROS-related mechanism seems to exacerbate TNF-α and NF- κβ effects on muscle wasting (Oudijk, 2003). TNF-α and ROS act in multiple ways. They have a common source in circulating leukocytes. Activation and dysfunction of leukocytes is shared by COPD, SAHS and DM. The activated leukocyte enhances the expression of adhesion molecules such as CD11b and CD18. This effect predominates in lung tissue if we look at COPD, while systemic endothelium is the main target in SAHS. In addition, exacerbations of COPD may deteriorate the antioxidant response, while ROS are particularly enhanced in SAHS when hypoxia is intermittent in a similar way to injury reperfusion syndrome (McNicholas, 2009). Because ROS production is also a direct effect of hyperglycemia, oxidative stress can be posed as a link between SAHS, DM, overlap syndrome and metabolic syndrome. MS is not so clearly identified in the particular case of COPD. A specific oxidative response in SAHS/ overlap may well account for this difference. Another effect of neutrophil dysfunction is the inactivation of antiproteases leading to airspace ephitelial damage and mucus hypersecretion. As we see, TNF-α / neutrophil axis is

mitogenesis activating protein kinases (MAP-k) perpetuating inflammation this way.

studies (Takabatake et al., 2000 in Sevenoaks & Stockley, 2006).

wasting (Sevenoaks & Stockley, 2006).

overlap syndrome is unknown.

**4.3 Oxidative stress** 

Fig. 1. Convergent pahogenesis of chronic obstructive pulmonary disorders, diabetes *mellitus* and metabolic syndrome. COPD: Chronic obstructive pulmonary disease; SAHS: Sleep apnea-hypopnea syndrome; DM: Diabetes *mellitus*; MS: Metabolic syndrome.

neurons. These authors observed a general and markedly higher sympathoexcitation in COPD patients when compared to SAHS, bronchiectasis or healthy subjects. The individual neurone firing probability and mean firing rate were comparable to those recorded in SAHS, but higher than those observed in the healthy group. This finding suggests that muscle vasoconstrictor response is sustained long-after intermittent hypoxia, as it would occur in SAHS patients. Permanent vasoconstriction causes further resistance to the airway flow in any chronic obstructive disorder that is not completely reversed by normoxia. With respect to DM, the noradrenalin liberation of spontaneously active neurons has also been observed in the isolated disease.

Obesity also increases the MSNA burst incidence, but at lower levels than those seen in COPD or SAHS. Multiple firing of single-unit neurones has not been shown in obese subjects. Advanced age neither seems to be an explanation for the MSNA hyperactivity linked to COPD.
