Brain-derived neurotrophic factor enhances histamine-induced airway responses and changes levels of exhaled nitric oxide in guinea pigs in vivo

Abstract

The neurotrophin brain-derived neurotrophic factor (BDNF) occurs in elevated levels during airway inflammation, including asthma and hypoxic lung injury, and has been suggested to be associated with airway hyperresponsiveness in these conditions. The aim of the present study was to examine whether airway responses to histamine challenge and levels of exhaled nitric oxide (NO) in vivo might be altered upon BDNF treatment. Pulmonary resistance, lung compliance, insufflation pressure, and levels of exhaled NO were measured in anaesthetized guinea pigs exposed to BDNF prior to challenge with histamine and with intact or inhibited endogenous NO production. BDNF pretreatment significantly enhanced histamine-evoked increase in pulmonary resistance and insufflation pressure, as well as the decrease in lung compliance. BDNF markedly accentuated the reduction in exhaled NO following histamine challenge. In animals with inhibited endogenous NO production BDNF induced a significantly earlier histamine-evoked increase in airway responses. The present data show that BDNF can induce an augmentation of histamine-evoked airway responses and reduce levels of NO in exhaled air in vivo. Endogenous NO seems to exert a braking action on BDNF-induced enhancement of airway responses and a reduced ability to release NO may be one mechanism for increased airway response during elevated BDNF levels. Taken together this indicates that BDNF may be of importance for airway hyperresponsiveness in vivo. The interaction between BDNF and airway NO formation, and its relation to airway responses, merit further investigation.

Introduction

Airway inflammation and airway hyperresponsiveness are characteristics of both asthma and hyperoxic lung injury. It has also been suggested that neuronal dysfunction and structural modifications in the airways, including bronchial smooth muscle hypertrophy, play an important role in the development of airway hyperresponsiveness in these conditions (Boulet et al., 1998, Denis et al., 2001, Hershenson et al., 1992). The exact relationship between airway inflammation and airway hyperresponsiveness remains unclear, but may involve various cells and mediators, such as cytokines, chemokines and growth factors like neuronal growth factors.

Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor belonging to the family of neurotrophins. The neurotrophins are polypeptides that exert their effects both in the immune- and nervous systems. The function of the neurotrophins in survival, development, differentiation, and maintenance of nerve cells has been the matter of extensive research (Lewin and Barde, 1996). In regard to respiratory pathobiology, BDNF has been reported in high concentrations in blood and locally in the airways of asthmatics, especially after allergen exposure (Noga et al., 2001, Virchow et al., 1998). These observations have also been confirmed in animal models of allergic asthma (Braun et al., 1999).

In the airways a wide range of cellular sources for BDNF have been suggested. Thus both structural cells like the airway epithelial cells, airway smooth muscle cells, lung fibroblasts, as well as mast cells and inflammatory cells like eosinophils and lymphocytes are able to synthesize and secrete BDNF (Braun et al., 1999, Kemi et al., 2006, Ricci et al., 2004). The enhanced levels of BDNF during allergic inflammation may originate from infiltrating immune cells like macrophages and airway epithelium (Braun et al., 1999) where it might support eosinophil survival during inflammation (Hahn et al., 2006, Nassenstein et al., 2003), whereas the peribronchial smooth muscle is suggested as the major source of increased BDNF production during hyperoxic exposure (Yao et al., 2005). BDNF has been described to elevate intracellular calcium and enhance histamine-induced increases in force in isolated airway smooth muscle (Prakash et al., 2006), but the functional role of BDNF in the airways in vivo is not fully elucidated.

We hypothesized that BDNF also in vivo may increase the responses to histamine and affect the airway responsiveness without an underlying chronic inflammation. To address this question, we investigated the ability of BDNF to increase airway responses to the bronchoconstricting agonist histamine in guinea pigs in vivo. We also investigated whether BDNF may alter levels of nitric oxide (NO) in the airways, since NO has been proposed to be an endogenous inhibitory messenger molecule in the airways with capacity to counteract acute bronchoconstriction evoked by exogenous agonists or allergen exposure (Belvisi et al., 1992, Persson et al., 1993, Persson and Gustafsson, 1993). Furthermore we examined whether inhibition of endogenous NO production might affect the BDNF induced changes in histamine-evoked airway responses. We here demonstrate that BDNF augmented airway obstruction responses to histamine and decreased levels of NO in exhaled air in vivo and that inhibition of endogenous NO production changed the character of the BDNF-induced increase in airway responses to histamine, in that the augmentation occurred much earlier.

We suggest that BDNF may be of importance for development of airway hyperresponsiveness in vivo and that endogenous NO production may be protective during this state.