Endogenous and exogenous glucocorticoid effects in a model of allergic airway inflammation

Sammanfattning: Allergic asthma and rhinitis are inflammatory diseases of the airways. Allergic asthma is characterized by eosinophilic inflammation, reversible bronchoconstriction and airway hyperresponsiveness, whereas patients with rhinitis suffer from nasal inflammation, leading to rhinorrhea and nasal congestion. Glucocorticoids (GCs) are one of the major drugs for asthma and rhinitis treatment and can regulate leukocyte trafficking and mediator release. The hypothalamus pituitary-adrenal (HPA) axis regulates the secretion of endogenous GCs, and is one of the major stress effector systems in the body. The main role for the HPA-axis is to facilitate the maintenance of neuroendocrine homeostasis, both at basal and pathological conditions. An understanding of the regulation and function of the HPA axis is important for the evaluation of pathological changes and possible side effects caused by GCs. In the studies presented in this thesis we have used a mouse model to investigate the effects of endogenous GC synthesis and GC receptor inhibition, as well as acute stress, and different doses of exogenous administered GCs on inflammatory cells in different cellular compartments in allergic airway inflammation. We also investigated the effects of acute stress on the neurotrophic mediator, nerve growth factor (NGF) in the airways, during allergic inflammation. In the first study (I), we investigated the effects of endogenous GCs on eosinophilic airway inflammation. Inhibition of GC release with metyrapone (ME) induced an increase of bone marrow eosinophilia and when the ME treatment was combined with a GC receptor antagonist (RU 486) the allergen-induced bone marrow eosinophilia was further enhanced. ME treatment also induced an increase of CD4+ T lymphocytes in the nasal mucosa, both when employed as a single treatment and in combination with RU 486. In the second study (II), timing and dose-dependent effects of dexamethasone (DEX) on eosinophilic airway inflammation were studied. This study provided evidence that a low dose of DEX (1 µg/kg) evoked a stronger inhibitory effect on the eosinophilic airway inflammation, as compared to the effect of the 500 times higher pharmacological dose (500µg/kg) if given before the allergen challenge. When administered simultaneously the allergen challenge, the two doses displayed similar effects. The third study (III), was focused on the effects of timing of a short acute stress on allergic airway inflammation in upper and lower airways. Short stress applied before an allergen challenge decreased the allergen-induced eosinophilia in bronchoalveolar lavage fluid and lungs and also the inflammation in the nasal tissue. No effects on eosinophilia or inflammation were seen when stress was applied after allergen challenge or as a double stress both before and after challenge. The protective effects, seen in the mice stressed prior to the allergen challenge, were GC-dependent. In the fourth study (IV), the aim was to assess how acute stress modulated NGF levels and eosinophils in the airways during non-allergic and mild allergic conditions. We found that short stress increased the levels of NGF locally in the airways in both allergic and non-allergic mice. We also demonstrated that airway eosinophils decreased when stress was applied after allergen-challenge in a model of mild airway inflammation. The stress-evoked increase in NGF and decrease in eosinophilia in the airways were dependent on endogenous GC-synthesis, as evident from pre-treatment with ME. In summary, these results indicate that endogenous GCs may have a protective effect in both upper and lower eosinophilic airway inflammation. Our studies also demonstrate that the inhibitory effect of GCs on the allergic inflammation is timing-dependent. By the use of a GC synthesis inhibitor, we show that the inhibitory effects on the eosinophilic airway inflammation during acute stress are GC-dependent. Acute stress increased local airway NGF and this effect is mediated by endogenous GC synthesis. Thus, we also conclude that NGF may function as a mediator in the psychoneuroimmunological stress-response.