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

Final Report Summary - AIRGAL (Physiological function and potential therapeutic utility of the neuropeptide galanin in airway inflammation)

Executive Summary:

The dramatic increase in the number of inflammatory lung diseases, such as severe asthma and chronic obstructive pulmonary disease (COPD), over the last decades is of great concern for the public health service world-wide. In addition to chronic handicap, these diseases also feature recurrent episodes of acute worsening of inflammatory symptoms, known as exacerbations, a leading cause for progressive lung impairment. Prevention and prompt management of exacerbations is strongly recommended since they often influence disease prognosis. While it is clear that the immune system plays a significant role in orchestrating the responses in lung inflammation, the limited efficacy of immune therapies suggests the involvement of additional mechanisms.

Over the last decades, the existence of a bi-directional network between immunogenic and neurogenic mechanisms in airway inflammation became evident. Neuronal activation, induced by sensory neuropeptides in the lung, causes pain and irritation, neurogenic inflammation, mucus secretion and reflex responses such as, cough, sneezing and bronchoconstriction. Thus it is not surprising that increased amounts of substance P, a neuropeptide which causes many of the typical changes observed in inflamed airways, were found in the sputum and bronchoalveolar lavage fluid (BALF) of patients with serve asthma.

The neuropeptide galanin is a 29 amino acid (30 human), C-terminally amidated peptide with a widespread distribution in the central and peripheral nervous systems of many mammalian species and a diversity of biological effects.

To date, three galanin receptors, referred to as GalR1, GalR2 and GalR3, have been identified. All three galanin receptor subtypes are members of the GPCR superfamily, but the subtypes have substantial differences in their functional coupling and subsequent signalling activities, which contributes to the diversity of physiological effects of galanin.

Among the variety of neuropeptides, that can be detected in the lung, the role of galanin is poorly defined. In mammalian airways, galanin is primarily present in bronchial glands, blood vessels and nerve fibers associated with the epithelium. Moreover, galanin was found to coexist with several other neuropeptides (substance P, neuropeptide Y, vasoactive intestinal peptide) in the pulmonary system, suggesting a complex network of multiple mediators and functions.

Consistent with the presence of galanin binding-sites around blood vessels galanin inhibits cutaneous plasma extravasion in the skin after antidromic C-fiber stimulation, substance P injection and coinjection of substance P with calcitonin-gene related peptide (CGRP) as well as injection of histamine and coinjection of histamine with CGRP. Accordingly, galanin-overexpressing transgenic mice displayed a significant decrease in cutaneous plasma extravasation upon activation of neurogenic inflammation induced by mustard oil. Recently we were able to show that galanin abolished the inflammatory oedema formation induced by co-injection of SP and CGRP in murine skin, most likely via vasoconstriction and inhibition of blood flow in the cutaneous microvasculature mediated via GalR3. In addition, accumulation of polymorphonuclear neutrophils (PMNs), upon induction of different inflammatory stimuli is disrupted in mice with a loss-of-function mutation in the galanin gene (galanin knockout, Gal KO).

The major aim of the fellow of AIRGAL was to determine the role of galanin in the pulmonary system, using state-of-the art in vitro and in vivo experiments.

Many lung diseases, such as severe asthma, COPD, cystic fibrosis (CF), bronchiectasis and infiltrative pulmonary diseases are associated with chronic neutrophilic inflammation. Activation of lung neutrophils leads to the release of granule proteins, including myeloperoxidase (MPO) and matrix metalloproteinase-9 (MMP-9), which contribute to bronchial inflammation and to structural changes such as peribronchiolar fibrosis and emphysema. None of the currently available therapies has any effect on the release and/or pathological activity of these cytotoxic enzymes.

Therefore, efficient strategies to curbing down neutrophil function and lowering neutrophil recruitment may represent the best way to counteract their central role in airway inflammation. We found, that galanin is eventually able to degranulate neutrophils and that galanin induces leukocyte recruitment at inflamed vessels. Additionally, we were able to show, that this effect is mediated through GalR3, as it can be blocked with the selective GalR3 antagonist SNAP 37889.

One of the most prominent immune cells found in the airways is represented by alveolar macrophages (AM). AMs constitute a unique subset of pulmonary macrophages, which serve as first line of defense against inhaled substances and play a crucial role in lung homoeostasis. This is mainly achieved via phagocytosis of foreign material and the secretion of a wide range of mediator molecules, including those involved in neutrophil recruitment.

In neonates, which are known to manifest increased susceptibility to lung infection, AM may represent a significant factor in the neonatal immunological response to infections, providing a compensatory mechanism for the deficiencies in specific neonatal immunity. When analyzing the expression of the galanin system on AM isolated at different developmental stages in rats, we found a profound expression of GalR3 on all stages, implicating an important role of these receptor on AM.