Chronic Obstructive Pulmonary Disease, inflammation and co-morbidity--a common inflammatory phenotype?

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is and will remain a major cause of morbidity and mortality worldwide. The severity of airflow obstruction is known to relate to overall health status and mortality. However, even allowing for common aetiological factors, a link has been identified between COPD and other systemic diseases such as cardiovascular disease, diabetes and osteoporosis. COPD is known to be an inflammatory condition and neutrophil elastase has long been considered a significant mediator of the disease. Pro-inflammatory cytokines, in particular TNF-alpha (Tumour Necrosis Factor alpha), may be the driving force behind the disease process. However, the roles of inflammation and these pro-inflammatory cytokines may extend beyond the lungs and play a part in the systemic effects of the disease and associated co-morbidities. This article describes the mechanisms involved and proposes a common inflammatory TNF-alpha phenotype that may, in part, account for the associations.

Figure 1

Pathogenic process implicated in muscle wasting in COPD. Circulating TNF-α present in some patients with COPD binds to peripheral muscle cell receptors stimulating the production of ROS and apoptosis. In addition the receptor binding stimulates NF-κB activation, possibly enhanced by ROS. Protein loss is caused directly via increased ubiquitin activity, and indirectly via decreased MyoD expression decreasing myofibril synthesis. Protein loss is amplified by a reduction in muscle use. This is the result of a reduction in IGF-1 production (leading to a decrease in myofibril synthesis), and an increase in ubiquitin activity. TNF-α – tumour necrosis factor alpha TNFR – tumour necrosis factor receptor ROS – reactive oxygen species NF-κB – nuclear factor kappa beta Ubq – ubiquitin IGF – insulin-like growth factor

Figure 2

The roles of TNF-α, adiponectin and NF-κB in the metabolic syndrome. [Adapted from Sonnenberg et al (41)] TNF-α secreted from adipose tissue in conjunction with circulating glucose, FFA and insulin stimulate NF-κB activation. This action is opposed by adiponectin (indicated by the broken line), also secreted from adipose tissue. Activation of the PPARγ pathway (for example by TZDs) has been shown to directly increase expression of adiponectin and reduce TNF-α. Further activation of NF-κB is induced through the resulting increase in inflammatory cytokines, adhesion molecules and oxidative stress, leading to the clinical manifestations of the metabolic syndrome. The metabolic syndrome is a constellation of cardiovascular risk factors that is associated with a trebling of risk of type 2 diabetes and a doubling of risk of cardiovascular disease. Several definitions have been proposed [80-83] leading to some confusion and differences in prevalence rates. The International Diabetes Federation have recently proposed a practical, globally applicable definition of the syndrome using waist circumference plus any two of raised triglycerides, reduced HDL-cholesterol, raised blood pressure and raised fasting plasma glucose [84]. TNF-α – tumour necrosis factor alpha NF-κB – nuclear factor kappa beta FFA – free fatty acid LDL – low-density lipoprotein PPARγ – peroxisome proliferator activated receptor gamma TZD – thiazolidenedione

Figure 3

The inflammatory processes involved in atherosclerotic plaque formation. CRP binds to endothelial cells via the Fcγ receptor and is internalized, facilitating monocyte binding via the production of MCP-1. Further activation leads to further cytokine release and differentiation of the monocytes into macrophages. In the presence of oxidized LDL, CRP aids the production of foam cells – the basis of an atherosclerotic plaque. CRP – C reactive protein TNF-α – tumour necrosis factor alpha IL-6 – interleukin-6 MCP1 – monocyte chemotactic protein 1 LDL – low density lipoprotein ROS – reactive oxygen species

Figure 4

The central role of TNF-α in co-morbidity associated with COPD. TNF-α appears to play a central role in the pathogenesis of COPD and other conditions that are increasingly being recognised as systemic inflammatory diseases. Certain TNF-α receptor polymorphisms are associated with increased severity of disease [85,86] and this may be due to enhanced TNF-α effects. CRP levels can be increased directly by TNF-α and other cytokines. Elevated CRP levels appear to be particularly crucial in the pathogenesis of cardiovascular disease. ROS released as a result of COPD may enhance the likelihood of developing cardiovascular disease, diabetes and osteoporosis. TNF-α – tumour necrosis factor – alpha CRP – C reactive protein ROS – reactive oxygen species