Airway allergic inflammation. A role of bone marrow and relationship to substance P
Airway inflammation, along with reversible airway narrowing and airway hyperresponsiveness, is a central pathophysiological feature of bronchial asthma. The airway inflammation in asthma is dominated by eosinophils, cells that originate in the bone marrow. However, the precise mechanisms of the interaction between the airways and the bone marrow in the inflammatory process are less well known.The aim of this thesis was to determine the contribution of newly produced eosinophils to airway allergic inflammation, and the mechanisms of enhanced eosinophilopoiesis induced by allergen exposure. Furthermore the relationship between eosinophilic airway inflammation and substance P was investigated.Ovalbumin-sensitised Balb/c mice were repeatedly exposed to allergen via the airway route. Newly produced cells were identified using the thymidine analogue bromodeoxyuridine (BrdU), which is incorporated into DNA during cell mitosis. Anti-IL-3, anti-IL-5 and anti-GM-CSF treatments were given either systemically or directly to the airways. Identification of IL-5-producing cells in the bone marrow was performed using FACS. Bone marrow CD3+ cells were enriched to evaluate IL-5 protein release in vitro. IL-5-receptor bearing cells were localised by immunocytochemistry. In the human studies, eosinophilic inflammation was evaluated in induced sputum from patients with asthma. Substance P (SP) concentration in induced sputum was measured by radioimmunoassay.Repeated airway allergen exposure caused prominent airway eosinophilia after 3-5 exposures, and increased the number of immature eosinophils in the bone marrow. Up to 78% of BAL granulocytes were BrdU-positive. Anti-IL-5 given intraperitoneally inhibited both bone marrow and airway eosinophilia. Intranasal administration of anti-IL-5 also reduced BAL eosinophilia, to some degree via inhibition of bone marrow eosinophilia. The combined inhibition of IL-3 and GM-CSF reduced bone marrow and airway eosinophilia. After three allergen exposures, CD3+ cells acquired from the bone marrow expressed and released IL-5 protein. Bone marrow cells, but not BAL eosinophils, displayed stainable amounts of the IL-5-receptor a-chain. The sputum SP concentration in patients with asthma was significantly higher than in healthy volunteers, and inversely related to the degree of airway narrowing. In asthmatic subjects, the sputum eosinophil content correlated with the SP concentration in induced sputum.In conclusion, these data suggest that the bone marrow is activated by airway allergen exposure, and that newly produced eosinophils contribute to a substantial degree to the induced airway eosinophilia. In asthmatic airways, eosinophils may contribute to airway inflammation partly in parallel to SP-mediated inflammatory mechanisms. IL-5 plays a crucial role for the bone marrow activation and the induction of airway eosinophilia. Anti-IL-5-treatment targeted to the bone marrow may be a useful therapeutic approach to inhibit eosinophilic inflammation in asthma.
Göteborgs universitet/University of Gothenburg
Department of Respiratory Medicine/Allergology
Avdelningen för lungmedicin/allergologi
Hjärt-Lungområdets konferensrum,Elevhemmet (entréplanet), Bruna Stråket 11, Sahlgrenska Sjukhuset, kl 09.00
Date of defence
Tomaki, Masafumi 1964-