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To clarify the involvement of serine proteases in the development of allergic airway inflammation, we investigated the effect of nafamostat mesilate, a serine protease inhibitor, in a murine model of allergic asthma. Mice were sensitized to ovalbumin (OA) with alum and then exposed to 1% OA for 30 min, three times every 4th day. Nafamostat mesilate was administered orally for 10 days during the allergen challenge. In sensitized mice, repeated allergen challenge induced an increase in tryptase proteolytic activity in bronchoalveolar lavage fluid (BALF). In addition, marked increases in the numbers of inflammatory cells, levels of T helper type 2 (Th2) cytokines and eotaxin in BALF, numbers of goblet cells in the epithelium, and level of OA-specific IgE in serum were observed after repetitive allergen inhalation. Treatment with nafamostat mesilate significantly inhibited not only increased proteolytic activities, but also increases in the numbers of eosinophils and lymphocytes in the BALF. Nafamostat mesilate also dose-dependently inhibited increases in the levels of interleukin-13 and eotaxin in BALF and goblet cell hyperplasia. These findings suggest that increased serine protease activity in the airways is involved in the development of antigen-induced allergic eosinophilic inflammation and epithelial remodeling in bronchial asthma.

Asthma is a chronic inflammatory disease characterized by variable bronchial obstruction, hyperresponsiveness, and by tissue damage known as airway remodeling. In the present study we demonstrate that interleukin (IL)-5 plays an obligatory role in the airway remodeling observed in experimental asthma. BALB/c mice sensitized by intraperitoneal injections of ovalbumin and exposed daily to aerosol of ovalbumin for up to 3 wk, develop eosinophilic infiltration of the bronchi and subepithelial and peribronchial fibrosis. The lesions are associated with increased amounts of hydroxyproline in the lungs and elevated levels of eosinophils and transforming growth factor (TGF)-beta1 in the bronchoalveolar lavage fluid. After 1 wk of allergen challenge, TGF-beta is mainly produced by eosinophils accumulated in the peribronchial and perivascular lesions. At a later stage of the disease, the main source of TGF-beta is myofibroblasts, identified by alpha-smooth muscle actin mAb. We show that all these lesions, including fibrosis, are abolished in sensitized and allergen-exposed IL-5 receptor-null mice, whereas they are markedly accentuated in IL-5 transgenic animals. More importantly, treatment of wild-type mice with neutralizing anti-IL-5 antibody, administered before each allergen challenge, almost completely prevented subepithelial and peribronchial fibrosis. These findings demonstrated that eosinophils are involved in allergen-induced subepithelial and peribronchial fibrosis probably by producing a fibrogenic factor, TGF-beta1.

Interleukin (IL)-5 is thought to play important roles in asthma and to be a potential therapeutic target. An intratracheal injection of murine recombinant IL-5 (3-30 microg/animal) induced a dose-dependent increase in the number of eosinophils in the bronchoalveolar lavage fluid of Brown Norway (BN) rats 24 h after administration. Bovine serum albumin (30pg/animal), used as reference material, did not cause any change. The reaction was not observed in F344 rats. The increase in the number of eosinophils did not accompany bronchial hyperreactivity in BN or F344 rats. Prednisolone (3-10 mg/kg, i.p.) and emedastine (30 mg/kg, p.o.) reduced the increased number of eosinophils induced by the IL-5 challenge. These results suggest that IL-5 is a potent inducer of eosinophils in the airway of BN rats. Prednisolone and emedastine are effective against IL-5-induced eosinophilia.

Background: The role of 5-lipoxygenase (5-LO) products in the asthmatic bronchoconstriction is evident. However, the role of 5-LO products in airway hyperresponsiveness (AHR) and airway inflammation is still under discussion. The aim of the present study is to investigate the role of leukotriene D[sub 4] (LTD[sub 4] ) in AHR and allergic airway eosinophilia in mice. Methods: The effect of LTD[sub 4] inhalation on antigen-induced AHR and airway eosinophilia was investigated in 5-LO gene-deficient mice. Results: After three inhalations of LTD[sub 4] , airway responsiveness to acetylcholine was not altered in normal or allergic wild-type and 5-LO knockout (KO) mice. In contrast, the number of eosinophils in 5-LO KO allergic mice increased to the level of wild-type allergic mice after the inhalation of LTD[sub 4] . These observations were confirmed by a histopathological study of the lungs. No change in the cytokine levels in bronchoalveolar lavage fluid and serum immunoglobulin levels was shown after LTD[sub 4] inhalation. Conclusion: These findings suggest that LTD[sub 4] plays a role in eosinophilic airway inflammation but not in AHR in mice.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

ABSTRACT The role of interleukin (IL)-4 in the development of allergen-induced airway inflammation and bronchial hyperresponsiveness (BHR) is still controversial. To investigate the role of IL-4 in the development of antigen-induced airway inflammation and BHR, we used two different inbred IL-4 gene-knockout mice; one was BALB/c, which is known to be a high IgE responder, and the other was C57BL/6, known to be a low IgE responder and a lower responder to acetylcholine (ACh) in the airways. Mice were immunized with antigen at intervals of 12 days. Starting 10 days after the second immunization, mice were exposed to antigen three times every fourth day. Twenty-four hours after the last antigen challenge, bronchial responsiveness to ACh was measured and bronchoalveolar lavage was performed. In sensitized BALB/c mice, repeated aeroallergen challenge induced dramatic eosinophilia in the airways and severe increases in bronchial responsiveness to intravenous ACh, along with increases in serum antigen-specific IgE. In contrast, immunized C57BL/6 mice, after antigen provocation, developed a minor influx of eosinophils into the airways and only moderate increases in bronchial responsiveness without antigen-specific IgE in serum, indicating that the genetic background influenced not only IgE synthesis, but also the degree of airway inflammation and BHR. Moreover, disruption of the IL-4 gene in both strains of mice abolished allergen-induced BHR, airway eosinophilia and IgE response. Together, these findings suggest that the differences in genetic background can directly influence the pathophysiology of bronchial asthma, including the role of IgE, and that IL-4 has a crucial role in the development of allergen-induced BHR independent of genetic background. [ABSTRACT FROM AUTHOR]

The effect of a newly synthesized compound, HSR-609, on rat experimental rhinitis was investigated. In the first part of the study, a new experimental nasal allergic late phase eosinophilia model in Brown Norway (BN) rats was investigated. The increase in the number of antigen inhalations resulted in the proportional increase in the number of inflammatory cells such as macrophages, eosinophils and neutrophils in the nasal cavity lavage fluid (NCLF) at 5 h after each inhalation. The number of inflammatory cells reached a maximum 8 h after the antigen perfusion. Submaximum response was observed at 5 h after the antigen provocation. In this system, the serum IgG and IgE antibody titers measured by homologous passive cutaneous anaphylaxis were 160 and 640, respectively. In the second part of the study, the effects of prednisolone, cetirizine and a newly synthesized amphoteric antiallergic agent, HSR-609, on this allergic late nasal eosinophilia and neutrophilia in BN rats were investigated. Prednisolone and HSR-609 significantly inhibited the increase in the number of eosinophils in the NCLF but not cetirizine. Furthermore, prednisolone showed the inhibition of the increase in the number of macrophages and neutrophils in NCLF. These results suggest that this late phase eosinophilia model in the nose of BN rats may be useful for investigating the therapeutic drugs for nasal allergy and a newly synthesized amphoteric antiallergic agent, HSR-609, may be useful for the treatment of allergic rhinitis with eosinophilia.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The effects of 7-[3-[4-(2-quinolinylmethyl)- 1-piperazinyl]propoxy]-2,3-dihydro-4H-1,4- benzothiazin-3-one (VUF-K-8788) on experimental asthmatic reactions in guinea pigs were investigated. VUF-K-8788 inhibited histamine-induced bronchoconstriction at the doses of 0.3 and 1 mg/kg per os (p.o.). VUF-K-8788 inhibited anaphylactic bronchoconstriction at doses between 0.01 and 1 mg/kg in passively sensitized guinea pigs. Terfenadine used as a reference drug also inhibited an antigen-induced bronchoconstriction. VUF-K-8788 at the doses of 0.3 and 1 mg/kg inhibited immediate- and late-phase asthmathic reactions in actively sensitized guinea pigs. Terfenadine inhibited only the immediate phase reaction. Moreover, VUF-K-8788 inhibited the infiltration of eosinophils and macrophages into bronchoalveolar lavage fluid in guinea pigs. These results indicate that VUF-K-8788 may be useful for the treatment of bronchial asthma. [ABSTRACT FROM AUTHOR]

Previous studies have reported that the mice passively sensitized with anti-dinitrophenol (DNP) IgE antibody exhibited IgE-mediated cutaneous reaction with an immediate phase response (IPR) at 1 h and a late phase response (LPR) at 24 h after the challenge of dinitrofluorobenzene (DNFB). We found that the third- phase inflammatory reaction with intense and persisting infiltration of eosinophils, named ‘very late phase reaction (vLPR)’, was induced following IPR and LPR in response to DNFB in actively and passively sensitized mice, and that the peak response of vLPR was at 8 days after the challenge. This reaction was slightly observed in non-sensitized mice. Since the accumulation of eosinophils in vLPR was markedly observed when compared with that of LPR at 24 h, the vLPR may be an important reaction in allergic diseases. The development of vLPR was partly decreased in mast cell-deficient WBB6F1-W/Wv mice and was absent in T cell-deficient BALB/c-nu/nu mice in passive sensitization. These results indicate that the vLPR in the triphasic cutaneous reaction may be mainly mediated by T cells and partially by mast cells and/or IgE antibody, and consequently lead to an intense ear swelling accompanying massive infiltration of eosinophils. [ABSTRACT FROM AUTHOR]