Pharmacological approaches for the discovery and development of new anti-inflammatory agents for the treatment of cystic fibrosis

Abstract

Some of the most important pathobiology in cystic fibrosis occurs not as a direct result of impaired chloride transport, but the downstream consequences of defective CFTR function, particularly the lung infection and inflammation that ultimately takes the lives of most patients. Interrupting the vicious cycle of infection and inflammation is effective in slowing the course of the disease, and antibiotics have long been the staple of pulmonary therapy. However, limiting the inflammatory response in the CF lung is also effective. High dose ibuprofen clearly retards progression of lung disease, but also entrains adverse events that mar its therapeutic utility, so alternative anti-inflammatory agents are necessary. Because of the remarkable therapeutic success of ibuprofen, consideration should be given to finding less toxic alternatives. However, it is also appropriate to consider the mechanisms by which the inflammatory response occurs in the CF lung, and identify sites to interrupt it. Sites at which therapeutic intervention is possible are the neutralization of cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, or IL-8 with specific antibodies or receptor antagonists, inhibition of the intracellular signaling cascades that result in cytokine production (for example, at the level of p38 MAP kinase), application of cytokines such as Il-10 that are themselves anti-inflammatory, or modulating the arachidonic acid cascade with inhibitors directed at leukotriene B(4). In addition, interventions designed to limit the consequences of the inflammatory response, such as protease inhibitors and reagents to limit the ill effects of DNA accumulation in airways, are in use. To limit adverse effect and concentrate the therapeutic effect, there may be value in targeting delivery of the therapeutic reagents to the inflamed site, either by specifically directing systemic delivery or by exploitation of the aerosol route. Treating the inflammatory response is important, for the data from the ibuprofen study show that the effects of anti-inflammatory therapy are additive or even synergistic with intensive conventional therapy and alter the rate of decline of pulmonary function, and therefore benefits for survival of patients with CF are to be expected.