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Chronic obstructive pulmonary disease (COPD) is a major global health burden and will become the third largest cause of death in the world by 2020 (Lopez and Murray, Nat Med 4(11):1241-1243, 1998). An exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, is the likely cause of a progressive airflow limitation. This inflammation, where macrophages and neutrophils are prominent, leads to oxidative stress, emphysema, small airway fibrosis and mucus hypersecretion. However, COPD responds poorly to current anti-inflammatory treatments including potent glucocorticosteroids which produce little or no benefit. COPD lungs may also become colonized with Gram negative and Gram positive bacteria which hasten lung function decline and, along with viruses and inhaled pollutants, are major triggers of recurrent debilitating exacerbations. COPD patients suffer recurrent acute exacerbations (AECOPD) caused by both viruses and bacteria.
Histological and bronchial biopsy studies show that patients with COPD have an increased number of neutrophils (Di Stefano et al, Am J Respir Crit Care Med 158(4):1277-1285, 1998; Retamales et al, Am J Respir Crit Care Med 164:469-473, 2001). In addition, BALF and sputum of COPD patients have a marked increase in neutrophils (Pesci et al, Eur Respir J 12(2):380-386, 1998; Keatings et al, Am J Respir Crit Care Med 153(2):530-534, 1996). Neutrophil numbers in bronchial biopsies and induced sputum are correlated with COPD disease severity (Di Stefano et al, 1998 supra, Keatings et al, 1996 supra) and with the rate of decline in lung function (Stanescu et al, Thorax 51(3):267-271, 1996). Neutrophils secrete serine proteases, including neutrophil elastase, cathepsin G and protease-3, as well as MMP-8 and MMP-9, which contribute to alveolar destruction and produce emphysema in laboratory animals (Stockely, Am J Respir Crit Care Med 160(5 Pt 2):S49-52, 1999; Barnes et al, Eur Respir J 22:672-688, 2003). Neutrophils migrate into the respiratory tract under the direction of neutrophil chemotactic factors, which include IL-8 (Barnes et al, supra 2003). Serine proteases are potent stimulants of mucus hypersecretion and may have an important role in the mucus hypersecretion seen in chronic bronchitis (Sommerhoff et al, J Clin Invest 85(3):682-289, 1990).
One cytokine involved in inflammatory reactions is granulocyte colony-stimulating factor (G-CSF) which is encoded by the CSF-3 gene. G-CSF is a hemopoietic growth factor that regulates the production of granulocytes (Nicola et al, Nature 314:625, 1985; Metcalf, International Journal of Cancer 25:225, 1980; Nicola et al, Journal of Biological Chemistry 258:9017, 1983). G-CSF mediates its effects through interaction with the G-CSF receptor (G-CSFR, encoded by the CSFR-3 gene), a member of the type I cytokine receptor superfamily (Demetri et al, Blood 78:2791-2808, 1991). Major biological actions of G-CSF in humans and mice, include increasing the production and release of neutrophils from the bone marrow (Souza et al, Science 232:61, 1986; Lord et al, Proc. Natl. Acad. Sci. USA 86:9499-9503, 1989), mobilizing hemopoietic progenitor cells from the marrow into the peripheral blood (Bungart et al, British Journal of Haematology 22:1156, 1990; de Haan et al, Blood 86:2986-2992, 1995; Roberts et al, Blood 89:2736-2744, 1997) and modulating the differentiation and effector functions of mature neutrophils (Yong et al, European Journal of Haematology 49:251-259, 1992; Colotta et al, Blood 80:2012-2020, 1992; Rex et al, Transfusion 35:605-611, 1995; Gericke et al, Journal of Leukocyte Biology 57:455-461, 1995; Xu et al, British Journal of Haematology 93:558-568, 1996; Yong, British Journal of Haematology 94:40-47, 1996; Jacob et al, Blood 92:353-361, 1998). G-CSF is used to treat neutropenia, as well as mobilization of haemopoietic stem cells (HSC) for autologous and allogenic stem cell transplantation (Welte et al, Blood 88:1907-1929, 1996).
There is an urgent and immediate need to develop new treatments for inflammatory conditions such as COPD, its exacerbated forms such as AECOPD and other pulmonary diseases characterized by or associated with infiltration of neutrophils.