Pde4 I

Alveolar macrophage

Neutrophil

Alveolar macrophage

Neutrophil

- Neutrophil elastase

Proteases Cathepsins

Matrix metalloproteinases

Alveolar wall destruction (Emphysema)

Mucus hypersecretion (Chronic bronchitis)

Fig. 11.4 Effects of phosphodiesterase 4 (PDE4) inhibitors in chronic obstructive pulmonary disease (COPD).

activity. Inhibition of these enzymes results in inhibition of inflammatory cells and relaxation of smooth muscle. Over 10 families of PDEs are now recognized, but the family most relevant to COPD inflammation is PDE4, since PDE4 inhibitors inhibit neutrophilic inflammation, but also inhibit macrophage and T-lymphocyte function [23] (Fig. 11.4). PDE4 inhibitors also have a bronchodilator action. A selective PDE4 inhibitor has recently been shown improve lung function and symptoms in patients with COPD [24]. The disadvantage of PDE4 inhibitors is that they cause nausea and vomiting, but more selective drugs have now been developed which are better tolerated.

The transcription factor nuclear factor-kB (NF-kB) is of critical importance for the persistence of chronic inflammation [25]. It regulates the synthesis of IL-8 and TNF-a, as well as adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), suggesting that NF-kB inhibitors might be beneficial in COPD. Several approaches to inhibition of NF-kB are now in development, but there are concerns that effective inhibition of NF-kB might impair host defence.

Neutrophil recruitment into the lungs and respiratory tract is dependent on adhesion molecules expressed on neutrophils and endothelial cells in the pulmonary and bronchial circulations. Neutrophil adhesion in response to chemotactic factors is characterized by expression of the b2 integrins CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) on the surface of the neutrophil and their interaction with their counterreceptors, including intercellular adhesion molecule-1 (ICAM-1), on endothelial cells. E-selectin on endothelial cells also interacts with sialyl-Lewisx on neutrophils. Bronchial biopsies of patients with COPD have demonstrated increased expression of E-selectin on vessels and ICAM-1 on epithelial cells [26]. Drugs that interfere with these adhesion molecules should therefore inhibit neutrophil inflammation in COPD and well tolerated selectin inhibitors have now been developed for clinical studies. However, there are concerns about this therapeutic approach for a chronic disease, as an impaired neutrophilic response may increase the susceptibility to infections.

There is increasing recognition that mitogen-activated protein (MAP) kinases may play an important role in chronic inflammation. One MAP kinase, p38 MAP kinase is important in release of inflammatory mediators such as TNF-a, and small molecule inhibitors of this enzyme have now been developed that might be useful in COPD if these drugs are well tolerated [27].

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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