Emma Michelle Campbell

PPAR‐α and ‐γ but not ‐δ agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF‐κB‐independent effect

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

Proteolytic activity of the house dust mite allergen Der p 1 enhances allergenicity in a mouse inhalation model

Background We have recently demonstrated that intraperitoneal immunization of mice with proteolytically active Der p 1, the major house dust mite allergen, results in a significant and selective enhancement of total and Der p 1‐specific IgE synthesis compared to mice immunized with proteolytically inactive Der p 1.