Blocking the CXCL10:CXCR3 axis for the treatment of COPD

There is a pressing need to develop new treatments for the chronic obstructive pulmonary diseases (COPD), chronic obstructive bronchitis and emphysema. World-wide, 600 million people suffer from COPD, with some three million dying from the disease each year. This serious healthcare problem is paralleled by a global market of US$2.8 billion. There is a particular need to develop drugs that control the underlying inflammatory and destructive processes that cause COPD as no currently available drug therapy reduces the relentless progression of COPD. In contrast to the enormous advances made in asthma management (see our recent overview of current and future asthma therapeutics) little significant progress has been made in COPD therapeutics.

COPD is characterized by an accelerated decline of lung function. This occurs in all individuals as a natural process of aging however the process is more rapid in smokers especially in a sub-set of smokers who are for whatever reason more susceptible to loss of function. There has been only slow progress in understanding the cell and molecular mechanisms of COPD. However, it is now recognized that this disease involves a chronic inflammation in small airways and lung parenchyma, with the involvement of neutrophils, macrophages and T-lymphocytes. This inflammation results in fibrosis with narrowing of small airways (chronic obstructive bronchitis) and lung parenchymal destruction due to the action of various proteases, such as neutrophil elastase and matrix metalloproteinases (emphysema). This inflammation is quite different from that seen in asthma, indicating that different treatments are likely to be needed.

Chronic pulmonary inflammation exists in the lungs of patients with COPD and CD8+ Tc1 type T lymphocytes have been implicated as key culprits in the pathogenesis, especially tissue remodeling, seen in COPD.

Chemokines are a superfamily of small molecular weight proteins that play a crucial role in cellular activation and proliferation and in leukocyte recruitment to sites of inflammation. T lymphocytes found in the lungs of patients with COPD have been reported to be positive for the chemokine receptor, CXCR3. Furthermore, elevated expression of both CXCR3 and its ligand, CXCL10, have been demonstrated in the peripheral airways of patients with COPD who smoke. CXCR3 expression in inflammatory cells is highly limited to activated, as opposed to resting, T lymphocytes. In particular, CXCR3 is highly expressed on CD8+ Tc1 type T lymphocytes. Stimulation of lymphocytic cells CXCR3 is thought to facilitate chemotaxis, adhesion, and diapedesis, suggesting that CXCL10 plays a key role in the infiltration of these T lymphocytes to the site of inflammation in COPD patients. CXCL10 is expressed by activated bronchial epithelial cells and neutrophils suggesting that interfering with CXCL10:CXCR3 binding represents a potentially effective approach to COPD however it remains unclear whether, despite its overexpression in COPD patients, CXCL10 exists at pathophysiologically relevant levels in these individuals, what cell types might be responsible for CXCL10 production in this disease, and how CXCL10 expression might be regulated in COPD. Researchers at GlaxoSmithKline in collaboration with the University of Pennsylvania Medical Center have recently addressed these issues.

In their recent FASEB Journal publication, Hardaker et al reported that the level of CXCL10 was increased by 8-fold in the lungs of COPD patients and in particular immunohistochemical evaluation of tissue from these patients demonstrated CXCL10 expression in infiltrating inflammatory cells within the lung parenchyma, in the mucus plug seen in the lumen, and in the airway smooth muscle layers. Of interest, in vitro stimulation of primary cultures of human airway smooth muscle with interferon-gamma or TNF-alpha (two inflammatory mediators that are abundant in COPD patients) resulted in the overexpression of CXCL10. Furthermore when administered together the two mediators were able to act synergistically in that the overexpression of CXCL10 was much larger than the sum increase of when either were added alone and overexpression was observed much earlier. The activation of NF-kappa B played a critical role in mediating the response to TNF-alpha alone and when administered together with interferon-gamma, but not in the response to the latter when administered without TNF-alpha.

These data therefore suggest that human airway smooth muscle may be a source of CXCL10, which is an important ligand for the CXCR3 receptor on lymphocytic cells, activation of which may result in the specific recruitment of effector T lymphocytes. Hence blocking the production of CXCL10 or its activation of CXCR3 receptors represents a candidate approach to the treatment of COPD. This study suggests that limiting CXCL10 production may be effected through the use of TNF-alpha blocking strategies or by inhibiting NF-kappa B. Humanized monoclonal TNF antibodies (infliximab) and soluble TNF receptors (etanercept) are the most tested approaches to blocking TNF-alpha and both are effective in other chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Both approaches should therefore also be effective in COPD however clinical studies evaluating this concept have yet to be published.

Entry date Thursday, January 22, 2004

Adapted from Hardaker et al, FASEB J. 2004 Jan; 18(1): 191-3. Epub 2003 Nov 03