Allergen-induced airway responsiveness

Gauvreau GM, Watson RM, Jordana M, Cockcroft D, O Byme PM, The effect of regular inhaled salbutamol on allergen-induced airway responses and inflammatory cells in blood and induced sputum. Am J Respir Crit Care Med 1997 156 1738-1745. 

Diamant Z, Grootendorst DC, Veselic-Charvat M, et al. The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clin Exp Allergy 1999 29 42-51. 

Bryce PJ, Geha R, Oettgen HC Desloratadine inhibits allergen-induced airway inflammation and bronchial hyperresponsiveness and alters T-cell responses in murine models of asthma. J Allergy Clin Immunol 2003 112 149-158. 

Elwood W, Lotval JO, Barnes PJ, Fan Chung K (1992) Effect of dexamethasone and cyclosporin A on allergen-induced airway hyperresponsiveness and inflammatory cell responses in sensitised Brown Norway rats. Am Rev Resp Dis 145 1289-1294 Elwood W, Barnes PJ, Sakamoto T, Fan Chung K (1993) Allergen-induced airway hyperresponsiveness in Brown Norway rat role of parasympathetic mechanisms. J Appl Physiol 75 279-284... 

Th2 cytokine IL-10 is an antiinflammatory cytokine that suppresses the secretion of proinflammatory cytokines (Dll), allergen-induced airway inflammation, and nonspecific airway responsiveness (T9). IL-13 shares a receptor component, signaling pathways, and many biological activities with IL-4. In fact, IL-13 is also an antiinflammatory cytokine and plays a unique role in the optimal induction and maintenance of IgE production and IgE-mediated allergic responses when IL-4 production is low or absent (DIO, W12). Moreover, IL-13 or IL-4 shows a synergistic effect with TNF-a or IL-5 on eosinophil activation (L20). Recently, IL-11 was found to be involved in the chronic remodeling seen in asthmatic airways and is associated with increasing severity of the disease (Ml6). 

T9. Tournoy, K. G., Kips, J. C., andPauwels, R. A., Endogenous interleukin-10 suppresses allergen-induced airway inflammation and nonspecific airway responsiveness. Clin. Exp. Allergy 30,... 

BRUSSELLE, G KIPS, J JOOS, G BLUETHMANN, H. PAUWELS, R. (1995) Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. American Journal of Respiratory Cell and Molecular Biology, 12, 254-259. 

Mangan NE, van Rooijen N, McKenzie AN et al. Helminth-modified pulmonary immune response protects mice from allergen-induced airway hyperresponsiveness. J Immunol 2006 176 138-147. 

The mechanism of allergen-induced increase in airway responsiveness is uncertain. Animal studies suggest the need for polymorphonuclear leukocytes (43). The relationship of this to the LAR, the relationship of the LAR to allergen-induced airway inflammation (see below), and the correlation between airway responsiveness and airway eosinophilia (44) have led to the hypothesis that allergen-induced increase in airway responsiveness is somehow caused by airway inflammation. In fact, until recently, measurement of allergen-induced increases... 

Tang C, Rolland JM, Ward C, Quan B, Walters EH. Allergen-induced airway reactions in atopic asthmatics correlate with allergen-specific IL-5 response by BAL cells. Respirology 1997 2 45-55. 

The role of IgE in the late asthmatic response has been established in human studies in which it has been shown that pretreatment of asthmatic subjects with rhuMAb-E25—a nonanaphylactogenic anti-IgE monoclonal antibody—attenuates the LAR (Fig. 1) (35). This study established a role for IgE in the LAR— a role that had been debated up to that point (60). It also provided suggestive evidence that anti-IgE treatment attenuates allergen-induced airway eosinophilia. 

Clark JM, Abraham WM, Fishman CE, Forteza R, Ahmed A, Cortes A, Wame RL, Moore WR, Tanaka RD. Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep. Am J Respir Crit Care Med 1995 152 2076-2083. 

Theophylline s predominant mode of action appears to be bronchocHlation. However, it has also been shown that prophylactic acHriinistration of theophylline provides some protection from asthma attacks and suppresses the late-phase response (67,68). Some researchers beHeve that at therapeutic semm concentrations theophylline may inhibit the development of airway inflammation (69). There are conflicting reports on the effect of theophylline on allergen-induced bronchial hyperresponsiveness some clinical stucHes report a reduction in hyper-responsiveness, others do not (69,70). Theophylline clearly does not reverse the general bronchial hyperresponsiveness over the course of long-term therapy (71). Because of the relationship between... 

Single dose or short-term treatment with aerosolized steroids inhibits both the late asthmatic response and allergen-induced bronchial hyperresponsiveness (45,92). However it does not affect the early asthmatic response nor does it induce bronchodilation (45,92). Long-term treatment with steroids protects against both the early and late asthmatic responses and also reduces bronchial hyperresponsiveness (44,71,86,93). Over time, the airways relax (dilate) and measures of airway function, such as forced expiratory volume in one second (FEV ), gradually return to almost normal levels. 

Bronchial asthma is defined as a chronic inflammatory disease of the lungs it affects an estimated 9 to 12 million individuals in the U.S. Furthermore, its prevalence has been increasing in recent years. Asthma is characterized by reversible airway obstruction (in particular, bronchospasm), airway inflammation, and increased airway responsiveness to a variety of bronchoactive stimuli. Many factors may induce an asthmatic attack, including allergens respiratory infections hyperventilation cold air exercise various drugs and chemicals emotional upset and airborne pollutants (smog, cigarette smoke). 

The monofunctional tryptase inhibitor APC-366 (Axys Pharmaceuticals) reduces the acute airway response and histamine release to allergen in a pig model of allergen-induced asthma [19]. APC-366 is also effective in a sheep model of allergen-induced asthma but was only poorly effective in asthma patients (proof-of-principle) [8], The compound was in clinical development phase II for asthma (inhalative). Although highly selective for tryptase over plasmin and plasma kal-likrein, APC-366 was not selective against thrombin and trypsin [13], Another monofunctional tryptase inhibitor is bis(5-amidino-2-benzimidazol-yl)methane (BABIM) which has been shown to be effective in the sheep. Further development of the compound was, however, discontinued, maybe because of the lack of selectivity over trypsin [13, 16, 17] (Figure 3.2.2). 

Bhagat R, Swystun VA, Cockcroft DW. Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine dose response. J Allergy Clin Immunol 1996 97(1 Pt l) 47-52. 

Cartier, A., Thomson, N.C., Frith, P.A., Roberts, R and Har-greave, F.E. (1982). Allergen-induced increase in bronchial responsiveness to H relationship to the late asthmatic response and change in airway calibre. J. Allergy Clin. Immunol. 70, 170-177. 

It is uncertain which vessels leak in the late phase response. Although venules are labelled with the tracer Monastral blue in a dog model of allergen-induced late phase response (Ohrui et al., 1992), no vessels are labelled in the late phase response evoked in guinea-pig airways by PAF (O Donnell et al., 1990). It is unclear whether this diflference is due to differences in the animal models or to limitations of the methods used to identify the leaky vessels. One reason for considering that the late phase leak may not be just a longer version of the early response is evidence that prolonged inflammatory stimuli... 

Murine model of pulmonary eosinophilic inflammation airway inflammation augmentation of allergen-induced T cell proliferation, increased Th2 cytokine (IL-4 and IL-13) and IgE production local inflammatory response ameliorated with impaired recruitment of eosinophils and inferior levels of IL-5 vitamin D could sustain Th2 response, leading to increased prevalence of allergy, but promising beneficial effects in airway eosinophilia [127]... 

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