Late phase response

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... 

Frequently, the EAR is followed by a late phase response 4-6 h later and it is caused by the pulmonary sequestration of eosinophils, neutrophils, mast cells, and T-lymphocytes. This leukocyte recruitment depends on mast cell-derived mediators such as TNFa and various chemokines, as well as on the expression of adhesion molecules on leukocytes (e.g. VLA-4, CD11/18) and vascular endothelial cells (e.g. VCAM-1, ICAM-1, E-selectin). Products of these leukocytes have several functions First, they cause the second phase of bron-choconstriction, mucus secretion, and airway swelling second, they cause tissue destruction third, they launch and entertain the chronic inflammation. 

In the late phase response, activated airway cells release inflammatory cytokines and chemokines, recruiting inflammatory cells into the lungs. The late phase response occurs 4 to 6 hours after the initial allergen challenge and results in a less intense bronchoconstriction as well as increased airway hyperresponsiveness and airway inflammation.6... 

Cromolyn and nedocromil are inhaled anti-inflammatory agents that block both the early- and late-phase response. Both agents are considered alternative therapies to inhaled corticosteroids for the treatment of mild persistent asthma however, both are less effective than low doses of inhaled corticosteroids.2,30 The exact mechanism of action of these agents is not understood, but they appear to inhibit mast cell mediator release as well as modulate other inflammatory responses.3... 

Eosinophil infiltration is a major feature of asthma and allergic reactions [203], These cells are not abundant during the acute phase of the response, but increase in number and account for 10-80% of the total cell infiltrate during the late phase. Furthermore, major basic protein (MBP), which is released from eosinophil granules, causes respiratory epithelial damage [204]. Since PAF is a potent activator of eosinophil functions [205], BN 52021 may interfere with the late phase response. 

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. 

Type III reactions are the result of antigen-antibody (IgG) complexes that accumulate in tissues or the circulation, activate macrophages and the complement system, and trigger the influx of granulocytes and lymphocytes (inflammation). This is sometimes referred to as the Arthrus reaction and includes postinfection sequelae such as rheumatic heart disease. Farmer s lung, a pneumonitis caused by molds has been attributed to both type III and type IV, and some of the late phase response (4-6 hours after exposure) in asthmatics may be the result of Arthrus-type reactions. 

Figure 10.4 Nasal symptom scores during late-phase response. = P = 0.04 for Herbal Blend and placebo areas over NSS curves = P = 0.007 Herbal Blend versus placebo at 6 h.

Charlesworth, E.N., Hood, A.F., Soter, N.A., Kagey Sobotka, A., Norman, P.S. and Lichtenstein, L.M. (1989a). Cutaneous late-phase response to allergen. Mediator release and inflammatory cell infiltration. J. Clin. Invest. 83, 1519-1526. 

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... 

Gundel, RH., Wegner, C.D. and Letts, L.G. (1992). Antigen-induced acute and late-phase responses in primates. Am. Rev. Respir. Dis. 145, 369-373. 

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