Early-Onset Inflammatory ResponsesIn Vivoto Adenoviral Vectors in the Presence or Absence of Lipopolysaccharide-Induced Inflammation

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Abstract
Adenoviral vectors (Ad) have potential for use in pulmonary gene transfer for treating cystic fibrosis (CF). However, Ad may induce inflammation even in the absence of gene expression. Endotoxin from gram-negative bacteria in the airways of CF patients may also induce inflammation, and may further inhibit vector delivery and gene transfer. We used a mouse model to study the time course of Ad-induced lung inflammation and to assess additivity with lipopolysaccharide (LPS)-induced inflammatory responses. C3H/HeJ endotoxin-resistant (RES) mice hyporesponsive to inflammatory stimuli and normoresponsive C3HeB/FeJ endotoxin-sensitive (SEN) mice were studied to characterize inflammatory responses that follow intratracheal instillation of inactivated Ad, with or without simultaneous inhalation exposure to LPS. Instillation of 10(10) Ad particles dramatically increased bronchoalveolar lavage fluid (BALF) concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 at 3 to 6 h and induced profound neutrophilia, maximal at 12 to 24 h. SEN mice had tenfold greater responses than did RES mice at 6, 12, and 24 h. Mice exposed to Ad alone, LPS alone, or Ad + LPS had significant inflammation at the 3-h time point as demonstrated by BALF neutrophils, TNF-alpha, and IL-6. With all three treatments, SEN mice had a five- to 300-fold greater response than did RES mice. Importantly, Ad + LPS yielded no greater inflammatory response than LPS without Ad. These data demonstrate that replication-deficient Ad induce early inflammation and LPS-induced inflammation is not augmented by concurrent treatment with Ad.