Inflammatory Mediators and Neuromodulators: Targeting in Asthma and Chronic Obstructive Pulmonary Disease

The most common diseases affecting respiratory tract are bronchial asthma and chronic obstructive pulmonary disease (COPD). Both pathologies involve the genesis of an inflammatory response that induces airway hyperresponsiveness (AHR) and obstruction. Differences between both may include the cellular component: eosinophilia in atopic asthma and neutrophilia in COPD and also the nature of AHR which is generally reversible in asthma whereas in COPD this phenomenon culminates with the complete reduction of airflow. Because it represents the major global cause of disability and death, countless efforts have been underway for decades to develop therapies to alleviate their symptoms. Despite the fact that asthma is the result of a Th2 response in which IgE antibody is the main effector mechanism, the use of antibodies against cytokines of this profile did not show effectiveness until now. This could be because asthma is a multifactorial disease, depends also on the differentiation of TCD8+ lymphocytes type Tc2/Tc17 during the chronicity of the process. In contrast to asthma, inhaled glucocorticoids in COPD have a limited effect in resolving inflammatory symptoms, which could explain the high dependence on noxious stimuli such as smoke that aggravates the obstructive disease. The drugs tested so far cover the two main aspects of these pathologies: inhibition of a) functionality or activation of inflammatory response or b) tissue remodeling. In the first place, systemic antagonist of H1 and H2 receptors were widely used for decades in asthma as antipruritic and central sedatives, however their anti-inflammatory effects were modest, despite their important local effects in allergic reactions affecting skin such as dermatitis, rhinitis and conjunctivitis where the integrity of the epithelial barrier is more important in its genesis. Also, montelukast, an antagonist of cysteinyl-leukotriene C4 appears to affect both the inflammatory response and lung structure being successfully used in pediatric asthma. On the other hand, therapies with β2-agonist or anticholinergic drugs, widely used in COPD, have been shown to improve airway inflammation thickening. This review aims to provide a comprehensive overview of the available literature on the novel therapeutic targets; histamine, acetylcholine and cysteinyl-leukotrienes, with emphasis on the benefits and disadvantages of these clinical trials.

Keywords: Acetylcholine, asthma, bronchodilators, COPD, histamine, inflammatory mediators, leukotrienes, muscarinic receptors, therapeutic strategies, β2-agonists.