1 Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that have been proposed to regulate inflammation by antagonising the nuclear factor-kB (NF-kB) signalling pathway. We investigated the role of PPARs using synthetic agonists in murine models of airway inflammation, and addressed the possible effect on NF-kB signalling in vitro using a human epithelial cell line, A549. 2 Sensitised BALB/c mice exposed to an aerosol solution of ovalbumin had an increased number of airway eosinophils, neutrophils and lymphocytes. When given intranasally an hour before the aerosol challenge, a PPAR-a (GW 9578) and PPAR-g (GI 262570) selective agonist as well as a dual PPAR-a/g (GW 2331) agonist selectively inhibited allergen-induced bronchoalveolar lavage eosinophil and lymphocyte but not neutrophil influx. In contrast, a PPAR-d agonist (GW 501516) was inactive. 3 When given intranasally an hour before challenge, PPAR-a and PPAR-g selective agonists as well as a dual PPAR-a/g agonist did not inhibit lipopolysaccharide-induced bronchoalveolar lavage neutrophil influx or tumour necrosis factor-a (TNF-a) and KC production. 4 In A549 cells, selective agonists for PPAR-a, -g and -d did not inhibit intracellular adhesion molecule-1 expression following stimulation with proinflammatory cytokines. In addition, IL-8 release and the activation of an NF-kB-responsive reporter gene construct were inhibited only at micromolar concentrations, suggesting that these effects were not PPAR-mediated. 5 Our in vivo data show that agonists of PPAR-a and -g, but not -d, inhibit allergen-induced bronchoalveolar lavage eosinophil and lymphocyte influx. In vitro data suggest that this effect might not be mediated by antagonism of the NF-kB pathway.

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Cytokine regulation during an allergic response can dictate the severity of the inflammation and resulting injury. In the present study, we have examined the systemic and local effects of IL-18, a Th1-associated cytokine, on a cockroach allergen-induced airway response. In initial studies, temporal increases in IL-18 levels were observed within the lungs. When IL-18 was neutralized systemically the allergen-associated eosinophil accumulation was significantly accelerated 5-fold by 8 h postchallenge, suggesting a regulatory role for IL-18. Recombinant IL-18 (200 ng) was instilled into the airway at the time of allergen challenge to examine whether a direct impact on local eosinophil accumulation could be induced. When IL-18 was instilled, a significant increase in peribronchial eosinophil accumulation was observed in allergic mice as well as in nonallergic mice. A possible mechanism was observed in a significant increase in eotaxin, but not other eosinophil chemotactic factors, in bronchoalveolar lavage fluid after IL-18 instillation. The role of eotaxin was confirmed using eotaxin −/− mice, which demonstrated significantly less eosinophil accumulation compared with littermate controls. IL-18 was subsequently shown to induce eotaxin production from bronchial epithelial cells and isolated macrophages in in vitro assays. The clinical relevance of these findings was determined in treated mice and demonstrated that neutralization of IL-18 exacerbated, whereas exogenous IL-18 had no effect on airway hyperreactivity. Altogether, these data demonstrate that IL-18 may have multiple functions during an immune response that differ depending upon the local or systemic effects.

These data underline the important role of the proteolytic activity of Der p 1 in driving the allergic response in the lungs.

The induction of airway hyperreactivity during allergic responses involves multiple ill-defined mechanisms. Recently a role for stem cell factor (SCF) in the development of allergic eosinophilic airway inflammation has been identified. In the present study we demonstrate that SCF has a role in both the inflammatory response and airway hyperreactivity. Despite continued efforts to understand the mechanisms that drive airway responses, morbidity because of asthma continues to rise.