The Early Asthmatic Response

The significance of the mast cell as a source of these mediators is supported by the observation that sodium cromoglycate, an inhibitor of mast cell degranulation, completely abolishes the early reaction (Pepys a d., 1968). 

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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. 

Inhibits degranulation of mast cells also inhibits release of histamine and SRS-A (a leukotriene) from the mast cell. This inhibits the early asthmatic response by stabilizing the mast cell also inhibits the late asthmatic response. It has no intrinsic bronchodilator, antihistaminic, anticholinergic, vasoconstrictor, or anti-inflammatory activity. 

Inhaled Allergen Challenge as a Model of Asthma 2.3.I Mast Cells and the Early Asthmatic Response... 

Mast cells release histamines, leukotrienes and other mediators of the inflammatory process. Mast cell stabilizer drugs inhibit the early asthmatic response and the late asthmatic response. They have no bronchodilator effect nor do they have any effect on any inflammatory mediators already released in the body. They are indicated for the prevention of bronchospasms and bronchial asthma attacks. They are administered by aerosol inhalation. The exact action of the drugs have not been determined. However, they are believed to have a modest effect in lowering the required dose of corticosteroids. The most common mast stabilizer dmgs are cromolyn (Intal) and nedocromil (Tilade). 

Swystun VA, Bhagat R, Kaha S, Jennings B, Cockcroft DW. Comparison of 3 different doses of budesonide and placebo on the early asthmatic response (EAR) to inhaled allergen. J Allergy Clin Immunol 1998 102 363-367. 

Cockcroft DW, McFarland CP, O Byrne PM, Manning P, Friend JL, Rutherford BC, Swystun VA. Beclometbasone given after the early asthmatic response inhibits the late response and the increased methacholine responsiveness and cromolyn does not. J Allergy Clin Immunol 1993 91 1163-1168. 

The bronchospasm that occurs immediately after aeroallergen inhalation in allergic asthmatic subjects is at least partly an IgE-mediated immediate hypersensitivity reaction (1). At least two lines of evidence support this mechanism for the early asthmatic response. Eirst, pretreatment with an anti-IgE monoclonal antibody attenuates the early phase response in asthmatic subjects (Fig. 1) (2,3). Second, analysis of bronchoalveolar lavage fluid collected immediately after air-... 

In summary, current information suggests that the mechanism of airway narrowing during the early asthmatic response is an acute bronchoconstrictor response caused mainly by an IgE-dependent immediate hypersensitivity reaction. Of the preformed and newly synthesized mediators released from mast cells during these reactions, the cysteinyl leukotrienes appear to be the most important in the pathogenesis of the EAR. 

Inflammatory disease associated with bronchial hyperactivity (BHR), bronchospasm, T mucus secretion, edema, and cellular infiltration. Early asthmatic responses (EAR) lasting from 30 to 60 min are associated with bronchospasm from the actions of released histamine and leukotrienes late asthmatic responses (LAR) involve infiltration of eosinophils and lymphocytes into airways - > bronchoconstriction and inflammation with mucus plugging. 

Early asthmatic responses (EAR) lasting firom 30 to 60 minutes are associated with bronchospasm from the actions of released histamine and leukotrienes. 

Figure 1 Allergen-induced isolated early asthmatic response (EAR). FEV, (L) is on the vertical axis and time (hr) post-aUergen inhalation on the horizontal axis. Inhalation of ragweed allergen extract caused a 30% fall in FEV, maximal at 10 minutes and resolved by 2 hours (sohd tine) the response following inhaled diluent is shown in the dotted line.

Cieslewicz G, Tomkinson A, Adler A, et al. The late, but not early, asthmatic response is dependent on IL-5 and correlates with eosinophil infiltration. J Clin Invest 1999 104 301-308. 

Omalizumab is a recombinant humanized monoclonal anti-IgE antibody that inhibits binding of IgE to receptors on mast cells and basophils, resulting in the inhibition of mediator release and attenuation of the early- and late-phase allergic response. It may be a treatment option for moderate to severe persistent asthmatics 12 years of age or older whose asthma is not controlled by inhaled corticosteroids and who have a positive skin test or in vitro reactivity to perennial allergens.37 Omalizumab significantly decreases inhaled corticosteroid use, number and length of exacerbations, and increases asthma-related quality of life.37... 

Mechanism of Action A mast cell stabilizer that prevents the activation and release of inflammatory mediators, such as histamine, leukotrienes, mast cells, eosinophils, andmonocytes.T herapeuticEffect Prevents both early and late asthmatic responses. Pharmacokinetics The extent of absorption is 7% to 9% of a single inhaled dose of 3.5 to 4 mg and 17% of multiple inhaled doses, with absorption largely from the respiratory tract. Although most of the inhaled dose is subsequently swallowed, only 2% to 3% is absorbed from the G1 tract. Less than 4% of the total dose is systemically absorbed following multiple doses of ophthalmic solution. Protein binding 89%. Not metabolized. Excreted in urine. Half-life 1.5-3.3 hr. 

Fahey JV, Fleming HE, Wong HH, Liu J, et al. 1997. The effect of an anti-IgE monoclonal antibody on the early-and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med. 155 1828-1834. 

Studies of omalizumab in asthmatic volunteers showed that its administration over 10 weeks lowered plasma IgE to undetectable levels and significantly reduced the magnitude of both the early and the late bronchospastic responses to antigen challenge. Clinical trials have shown repeated intravenous or subcutaneous injection of anti-IgE MAb to lessen asthma severity and reduce the corticosteroid requirement in patients with moderate to severe disease, especially those with a clear environmental antigen precipitating factor, and to improve nasal and conjunctival symptoms in patients with perennial or seasonal allergic rhinitis. 

Challenge of sensitized subjects with inhaled allergen has been a vital experimental approach in asthma research since the first bronchoprovocation studies were performed by Max Samter in Berlin in 1933. Allergen inhalation results in an early bronchoconstrictor ( asthmatic ) response (EAR) at 5 to 10 minutes lasting up to an hour and, in about half of subjects, a late bronchoconstrictor response (LAR) starting at 2 to 3 hours and lasting for 12 to 24 hours (Pepys, 1973). 

The exacerbation of asthmatic responses is most frequently caused by a pulmonary viral infection, such as influenza, rhino, or adenovirus infections (81-89). Recent data has indicated that rhinoviral infections are the most common cause of severe asthma exacerbations. In addition to exacerbating asthmatic responses, severe respiratory syncytial virus (RSV) infections early in childhood appears... 

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