Peptide and non-peptide bradykinin receptor antagonists: role in allergic airway disease.

Kinins are proinflammatory peptides that mediate a variety of pathophysiological responses. These actions occur through stimulation of two pharmacologically distinct receptor subtypes B1 and B2. In both human and animal airways, the majority of kinin-induced effects including bronchoconstriction, increases in vascular permeability and mucus secretion and cholinergic and sensory nerve stimulation appear to be bradykinin B2-receptor mediated. Peptidic and non-peptidic receptor antagonists have been developed as potential therapeutic agents. These antagonists are effective in blocking kinin-induced effects in a variety of animal models and in some instances, have been used effectively in animal models of allergic airway disease to alleviate allergen-induced pathophysiological airway responses. This review summarizes relevant studies supporting the evidence that bradykinin B2 receptor antagonism and/or upstream inhibition of tissue kallikrein will be beneficial in the treatment of inflammatory airway diseases.

Future directions in the pharmacologic therapy of chronic obstructive pulmonary disease.

Current therapy for chronic obstructive pulmonary disease (COPD) fails to alter its relentless progression. This remains a significant challenge and unmet need. A recent advance is the demonstration that treatment with a fixed dose of an inhaled corticosteroid and a long-acting beta2-agonist in COPD improves lung function and quality of life, and reduces exacerbation more effectively than either drug alone. Other improvements include the introduction of tiotropium, a once-daily anticholinergic. In advanced clinical development are other once-daily bronchodilators and combinations of anticholinergic drugs and beta2-agonists. Increased understanding of the pathogenesis of COPD has led to novel drugs aimed at inhibiting targets, including phosphodiesterase 4, proteases, and various inflammatory mediators. Furthermore, COPD is increasingly seen as a systemic disorder or, indeed, may be a pulmonary manifestation of a complex pathophysiologic response to chronic inhalation of toxic irritants and associated with aging. Future therapy may involve better understanding of how best to target existing drugs used to treat cardiovascular disorders associated with smoking, such as atherosclerosis and hypercoagulability, and the development of new drugs that target systemic and metabolic manifestations that either result from or coexist with chronic lung inflammation, hypoxia, and cardiovascular disease in COPD.

Exacerbations and progression of disease in asthma and chronic obstructive pulmonary disease.

Exacerbations, characterized by an increase in patients' symptoms above baseline, are characteristic of both chronic obstructive pulmonary disease (COPD) and asthma. Prevention of exacerbations and their expedient treatment are major goals for reducing the morbidity and cost of both conditions. Exacerbations, however, may also adversely affect the natural history of these disorders, perhaps by contributing to increased rates of lung function decline, systemic effects, and premature mortality. Although the available information is limited, the course of COPD is affected adversely by exacerbations in multiple ways. First, exacerbations likely lead to structural alterations in the lung and to permanently worsened airflow. Second, health status is adversely affected by exacerbations, and although the mechanisms are unclear, the effects are long lasting and may be irreversible. Less is known in asthma about the effect of exacerbations on natural history, but many of the same pathogenetic processes involved in COPD exacerbations likely play a role in some subjects with asthma as well. Future studies of how exacerbation affects the "natural history" of asthma and COPD will require a better understanding of the heterogeneity of exacerbations but promises to identify new therapeutic strategies to treat these disorders.

Current and future pharmacologic therapy of exacerbations in chronic obstructive pulmonary disease and asthma.

Exacerbations are an important cause of the morbidity and mortality associated with asthma and chronic obstructive pulmonary disease. Newer therapies include long-acting beta(2)-agonists, which are more effective than short-acting bronchodilators. Inhaled corticosteroids and, in asthma, leukotriene receptor antagonists may have roles in the early phase of exacerbation as an alternative to or added to oral prednisolone. In the future, combinations of long-acting beta(2)-agonists and anticholinergic bronchodilators may offer additive clinical benefits. However, although the treatment and prevention of exacerbations of chronic obstructive pulmonary disease and asthma have been improved by using combinations of known therapies, further research addressing the underlying etiology as well as molecular and pathophysiologic mechanisms of exacerbation is needed to better target novel therapies to the appropriate patient populations and to develop new therapeutic strategies.

Synthetic serine elastase inhibitor reduces cigarette smoke-induced emphysema in guinea pigs.

To test whether a serine elastase inhibitor could prevent or reduce emphysema, we exposed guinea pigs to cigarette smoke acutely, or daily for 6 months, and treated some animals with the neutrophil elastase inhibitor ZD0892. Acute smoke exposure increased lavage neutrophils and increased desmosine and hydroxyproline, measures of elastin and collagen breakdown; all these measures were reduced by ZD0892. Long-term smoke exposure produced emphysema and increases in lavage neutrophils, desmosine, hydroxyproline, and plasma tumor necrosis factor alpha (TNF-alpha). ZD0892 treatment returned lavage neutrophils, desmosine, and hydroxyproline levels to control values, and decreased airspace enlargement by 45% and TNF-alpha by 30%. Animals exposed to smoke for 4 months and then to smoke plus ZD0892 for 2 months were not protected against emphysema. Mice exposed to smoke showed increases in gene expression of neutrophil chemoattractant macrophage inflammatory protein-2, macrophage chemoattractant protein-1, and TNF-alpha at 2 hours along with increased plasma TNF-alpha; ZD0892 prevented the increases in macrophage inflammatory protein-2 and macrophage chemoattractant protein-1 expression and reduced plasma TNF-alpha levels to baseline. These data demonstrate that a serine elastase inhibitor ameliorates the inflammatory and destructive effects of cigarette smoke, and that these effects are mediated in part by neutrophils and by smoke-driven TNF-alpha production.