AIRGAL

Physiological function and potential therapeutic utility of the neuropeptide galanin in airway inflammation

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 Obiettivo del progetto (Objective)

'The results of studies of the physiological and pathophysiological effects of peptides have guided the development of two principal classes of therapeutic agents: small molecules able to block the action of peptide receptors and synthetic peptides mimicking the actions of endogenous molecules. Within this arena, the effects of neuropeptides on the central nervous system (CNS) have been studied intensively for more than 20 years, leading to several therapeutic products that are in clinical development. However, it is now clear, that the actions of neuropeptides are far more diverse than previously thought. Another area with great pharmacologic potential encompasses the peripheral actions of the neuropeptide galanin. Lately, galanin has been shown to exhibit potent anti-inflammatory action in the skin and recent data indicate that galanin is also involved in the physiology and the immune system of the airways. Consequently, we hypothesise that galanin is a crucial regulator of airway inflammation and vascular tone in the lung. We further propose that galanin exerts its effects at different cellular levels within the pulmonary system. The aim of this study is to determine novel/specific functions and sites of action of galanin in the respiratory system and to evaluate the therapeutic potential of galanin on airway inflammation and hyperreactivity. To achieve these specific aims we will take a multidisciplinary approach, employing molecular and cell biology, pharmacology, in vivo animal model and clinical research. The outcomes of this study will precisely define the role of galanin in the respiratory system and may suggest novel therapeutic strategies for the control of asthma, chronic bronchitis or other inflammatory pulmonary disorders. The findings from this research may also be relevant to the process of chronic inflammation in other organs, such as skin, joints and the gastrointestinal tract.'

Introduzione (Teaser)

Over the past few years there has been a dramatic increase in airway inflammatory diseases such as asthma and chronic obstructive pulmonary disease. European research has been finding therapeutic approaches using neuropeptides.

Descrizione progetto (Article)

Accumulating evidence points towards a strong connection between immune and neurogenic mechanisms in airway inflammation. This is further supported by the limited therapeutic efficacy of immune therapies.

Asthma patients have higher levels of substance P, a neuropeptide that causes the pathology associated with inflamed airways. Another neuropeptide of widespread distribution, galanin is also encountered in the lung but it seems to counteract inflammation. Evidence so far indicates that it restricts blood flow and thus prevents immune cells from reaching the lungs and causing inflammation. Furthermore, mice deficient in galanin are unable to recruit neutrophils following an inflammatory stimulus.

Based on these observations, researchers of the EU-funded AIRGAL project set out to investigate the function of galanin in the pulmonary system. They were particularly interested in the impact of galanin on neutrophil function. Neutrophils are actively involved in bronchial inflammation and tissue alterations through the release of myeloperoxidase (MPO) and matrix metalloproteinase-9 (MMP-9) enzymes.

During the AIRGAL study, it became evident that galanin works through the receptor GAL3 by modulation of neutrophil function and inducing white blood cell recruitment at inflamed vessels. Additionally, galanin might be implicated in the recruitment of alveolar macrophages, the first line of defence against inhaled substances and central to lung homoeostasis.

Taken together, the delineation of the role of galanin in inflammation provides new therapeutic windows for inflammatory pulmonary diseases. Since alveolar macrophages are important for neonatal immunological responses, the outcome of the AIRGAL study may help to reduce their susceptibility to lung infection.