Allergen‐induced murine upper airway inflammation: local and systemic changes in murine experimental allergic rhinitis

Abstract

SUMMARYThe role of in¯ammatory effector cells in the pathogenesis of airway allergy has been the subject of much investigation. However, whether systemic factors are involved in the development of local responses in both upper and lower airways has not been fully clari®ed. The present study was performed to investigate aspects of the pathogenesis of isolated allergic rhinitis in a murine model sensitized to ovalbumin (OVA). Both upper-and lower-airway physiological responsiveness and in¯ammatory changes were assessed, as well as bone marrow progenitor responses, by culture and immunohistological methods. Signi®cant nasal symptoms and hyper-responsiveness appeared after intranasal OVA challenge (P<0 . 0001 and P<0 . 01, respectively), accompanied with signi®-cant nasal mucosal changes in CD4+ cells (P<0 . 001), interleukin (IL)-4 + cells (P<0 . 01), IL-5 + cells (P<0 . 01), basophilic cells (P<0 . 02) and eosinophils (P<0 . 001), in the complete absence of hyper-responsiveness or in¯ammatory changes in the lower airway. In the bone marrow, there were signi®cant increases in CD34 + cells, as well as in eosinophils and basophilic cells. In the presence in vitro of mouse recombinant IL-5, IL-3 or granulocyte±macrophage colony-stimulating factor (GM-CSF), the level of bone marrow eosinophil/basophil (Eo/Baso) colony-forming cells increased signi®cantly in the OVA-sensitized group. We conclude that, in this murine model of allergic rhinitis, haemopoietic progenitors are upregulated, which is consistent with the involvement of bone marrow in the pathogenesis of nasal mucosal in¯ammation. Both local and systemic events, initiated in response to allergen provocation, may be required for the pathogenesis of allergic rhinitis. Understanding these events and their regulation could provide new therapeutic targets for rhinitis and asthma.

The Eotaxin Chemokines and CCR3 Are Fundamental Regulators of Allergen-Induced Pulmonary Eosinophilia

“…Eosinophil CFU analysis was performed as described previously (38). In brief, nonadherent low-density mononuclear cells (1 ϫ 10 5 ) were cultured at 37°C and 5% CO 2 in 35 ϫ 10-mm tissue culture dishes in 1.0 ml of Methocult, 20% FCS, and 5.0 ng/ml recombinant mouse IL-5.…”

Effects of a cysteinyl leukotriene receptor antagonist on eosinophil recruitment in experimental allergic rhinitis

“…12 Briefly, OVA sensitization was achieved by administering 40 lg ⁄kg OVA (Sigma, St Louis, MO), diluted in sterile normal saline with aluminum hydroxide gel (alum adjuvant, 40 mg ⁄kg), to animals, four times by intraperitoneal (i.p.) injection on days 1, 5, 14 and 21.…”

“…To investigate the effects of in vivo administration of the cysLT1-R antagonist on eosinophil progenitor proliferation, differentiation and maturation, ex vivo analysis of bone marrow colony-forming assays in methylcellulose, an established functional assay of progenitor numbers and responsiveness to specific differentiation-inducing cytokines in humans and several animal models, [12][13][14][15][16] NAMNC, rmIL-3 (1 ng ⁄ml) with 5 · 10 4 NAMNC, or rm granulocyte-macrophage colony-stimulating factor (GM-CSF) (1 ng ⁄ml) with 2AE5 · 10 4 NAMNC. After 6 days, colonies of greater than 40 cells were counted using inverse microscopy, and Eo ⁄Baso-colony-forming units (CFU) were classified using morphological and histological criteria (tight, compact, round refractile cell aggregates).…”

“…NHR was expressed as the limiting concentration of histamine (log 10 pg ⁄ml), as previously described. 12 Statistics For all cell counts of stained slides, the slides were read randomly and in a blinded manner. Eo ⁄Baso CFU counts were also obtained by two independent observers who were blinded to plate conditions.…”

“…10 Recent studies in murine models, including those which we have developed, indicate that the extent of the tissue eosinophilic response is related, at least in part, to eosinophil differentiation in the bone marrow. 11,12 Given this, and the evidence of expression of cysLT1-R by CD34 + progenitors, 5 targeting the haemopoietic response may be an important mechanism underlying the anti-inflammatory effects of leukotriene antagonists.…”