Agent Name	Discussion
Mucolytic agents	Because mucus hypersecretion and impaired mucociliary clearance are characteristic of chronic bronchitis, attempts are being made to speed the transport of mucus up the bronchiotracheal tree Wegner (2001). Oral expectorants such as guaifenesin are of little benefit in chronic obstructive pulmonary disease. N-acetylcysteine is an orally administered glutathione precursor that reduces the sulfhydryl bonds of mucus proteins. It has been shown to thin the sputum without producing significant improvement in pulmonary function. Preliminary studies suggest that n-acetylcysteine may reduce the frequency of acute exacerbations, an action that may be related to its efficacy as an antioxidant.
Heliox	Heliox is a mixture of helium and oxygen that changes pulmonary airflow from turbulent to laminar. It has been shown to decrease the work of breathing in severe, stable, chronic obstructive pulmonary disease and may potentially be useful in the treatment of acute exacerbations of chronic bronchitis Chitkara and Sarinas (2002), Rodrigo et al (2002).
Phosphodiesterase inhibitors	Phosphodiesterase-4 (PDE-4) is a cyclic AMP-specific phosphodiesterase that predominates in pro-inflammatory and immune cells. Cilomilast is a new, orally active, selective inhibitor of PDE-4. Initial studies of cilomilast revealed significant functional improvement of chronic obstructive pulmonary disease (COPD) with minimal side effects Giembycz (2001). There is a significant decrease in the number of CD8+ and CD68+ inflammatory cells characteristic of COPD without alteration of sputum values or FEV-1 Gamble et al (2003).
Novel anticholinergic agents	Tiotropium is an inhaled anticholinergic that is available in Europe and is pending FDA approval in the United States Barnes (2003). It exhibits very slow dissociation from M-1 muscarinic receptors and M-3 muscarinic receptors, allowing it to provide once-daily dosing and a greater degree of stability in lung function than ipratropium. Tiotropium may be useful in acute or chronic bronchitis.
Leukotriene receptor antagonists	Leukotriene B-4 (LTB-4) is a mediator of neutrophilic inflammation that is elevated in the sputum of persons with chronic bronchitis. Several antagonists of LTB-4 receptors are in clinical development and may be useful in the treatment of chronic bronchitis Kilfeather (2002).
Cytokines and cytokine inhibitors	A number of agents that act through cytokine pathways that mediate the symptoms of chronic obstructive lung disease (COPD) are under investigation Barnes (2003), Reid and Sallenave (2003). Interleukin-10 (IL-10), an anti-inflammatory cytokine, decreases in those with COP D. Clinical trials of IL-10 in various inflammatory disorders are underway. IL-10 may hold promise in chronic bronchitis as well. Interleukin-8 (IL-8) is a neutrophil-attracting cytokine that is elevated in the sputum of persons with COP D. Inhibitors of IL-8 and antagonists of its receptor, CXCR2, are being developed and may be useful in the treatment of chronic bronchitis. Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine that activates various immune cells and stimulates the production of inflammatory cytokines and other mediators. Its levels are elevated in the sputum of individuals with COP D. Monoclonal antibodies directed against TNF-alpha, such as infliximab and recombinant soluble TNF-alpha receptor (etanercept) are effective in rheumatoid arthritis and other inflammatory disorders and may be useful in the management of chronic bronchitis.
Inhibitors of oxidative stress	N-acetylcysteine is a cysteine donor, enhancing the production of the antioxidant glutathione and decreasing oxidative stress. It has been shown to reduce the frequency of acute exacerbations of chronic bronchitis Wegner (2001). Additional antioxidants, such as stable glutathione compounds and superoxide dismutase analogs, are in clinical development. Inducible nitric oxide synthetase (iNOS) is responsible for the production of peroxynitrite, a potent oxidative species released during inflammation. Inhibitors of iNOS are under development and may be useful in the treatment of chronic bronchitis.
Protease inhibitors	Inhibitors of proteases (e.g., elastase) that are released by neutrophils during the inflammatory processes of chronic obstructive pulmonary disease are under development Barnes (2003). These compounds may slow the progression of emphysema that accompanies certain cases of chronic bronchitis.
Inhibitors of inflammatory signal transduction	The p38 mitogen-activated protein (MAP) kinase is involved in the expression of inflammatory cytokines and proteases involved in chronic bronchitis. Inhibitors of MAP kinase have been developed and may be useful in treating chronic bronchitis Barnes (2003). Inhibitors of phosphoinositide-3 kinase-gamma (PI-3Kgamma), an enzyme involved in neutrophil activation, may also be of value. Inhibitors of the NF-kappaB signaling pathway are in development and may be tested for the treatment of chronic bronchitis.