Inflammation and infection in naive human cystic fibrosis airway grafts

Exacerbated inflammation is now recognized as an important component of cys tic fibrosis (CF) airway disease. Whether inflammation is part of the basic defect in CF or a response to persistent infection remains controversial. We addressed this question using human fetal tracheal grafts in severe comb ined immunodeficient mice. This model yields histologically mature, and mos t importantly, naive CF and non-CF surrogate airways, Significant inflammat ory imbalance was found in naive CF airway grafts, including a highly incre ased intraluminal interleukin 8 content (CF: 10.1 +/- 2.2 ng/ml; non-CF: 1. 2 +/- 0.6 ng/ml; P < 0.05) and consistent accumulation of leukocytes in the subepithelial region (P < 0.001). CF airway grafts were not histologically affected until challenged with Pseudomonas aeruginosa, which provoked: (1) early (before 3 h) and massive leukocyte transepithelial migration, (2) in tense epithelial exfoliation, and (3) rapid progression of bacteria toward the lamina propria, In non-CF grafts, these three sets of events were not o bserved before 6 h. Using a model of naive human airways, we thus demonstra te that before any infection, CF airways are in a proinflammatory state. Af ter infection, the basal inflammatory imbalance contributes to exert severe damage to the mucosa, paving the way for bacterial colonization and subseq uent steps of CF airway disease.