G551D CF mice display an abnormal host response and have impaired clearance ofPseudomonaslung disease

Abstract

Several cystic fibrosis (CF) mouse models demonstrate an increased susceptibility to Pseudomonas aeruginosa lung infection, characterized by excessive inflammation and high rates of mortality. Here we developed a model of chronic P. aeruginosa lung disease in mice homozygous for the murine CF transmembrane conductance regulator G551D mutation that provides an excellent model for CF lung disease. After 3 days of infection with mucoid P. aeruginosa entrapped in agar beads, the G551D animals lost substantially more body weight than non-CF control animals and were less able to control the infection, harboring over 40-fold more bacteria in the lung. The airways of infected G551D animals contained altered concentrations of the inflammatory mediators tumor necrosis factor-alpha, KC/N51, and macrophage inflammatory protein-2 during the first 2 days of infection, suggesting that an ineffective inflammatory response is partly responsible for the clearance defect.

Increased susceptibility of purinergic receptor-deficient mice to lung infection withPseudomonasaeruginosa

“…Increased susceptibility of purinergic receptor-deficient mice is similar to what has been reported for several cystic fibrosis mice (G551D, S489X) (27,40). Similar to G551D CF mice, concentration of MIP-2 was lower in P2Y 1 /P2Y 2 Ϫ/Ϫ mice following challenge with intratracheal P. aeruginosa (27). However, unlike S489X CF mice challenged with intratracheal P. aeruginosa-laden agarose beads (39), levels of TNF-␣ were not significantly different between P2Y 1 /P2Y 2 Ϫ/Ϫ and WT mice.…”

“…Other causes of mortality were not excluded in the current study. Increased susceptibility of purinergic receptor-deficient mice is similar to what has been reported for several cystic fibrosis mice (G551D, S489X) (27,40). Similar to G551D CF mice, concentration of MIP-2 was lower in P2Y 1 /P2Y 2 Ϫ/Ϫ mice following challenge with intratracheal P. aeruginosa (27).…”

Role of Cftr genotype in the response to chronic Pseudomonas aeruginosa lung infection in mice

“…Cystic fibrosis mice respond to challenge with mucoid P. aeruginosa-laden agarose beads with a higher death rate and greater inflammatory response in the BAL fluid than mice with at least one normal cystic fibrosis allele (9,10,17). This has been demonstrated for cystic fibrosis mice bearing the S489X mutation both backcrossed to the C57BL/6 background (9) and on a mixed genetic background of 129P2 and C57BL/6 (10) and for cystic fibrosis mice bearing the G551D mice on a mixed genetic background of CD-1 and 129/Sv (17), in three different laboratories, each with one of two mucoid clinical strains of P. aeruginosa.…”

“…The exact link between the CFTR defect and the permissive nature of the cystic fibrosis lung to acquiring and maintaining chronic lung infection with P. aeruginosa is unknown. The pathophysiological cascade that leads to lung disease probably includes trapping of bacteria in abnormal airway surface fluid and secretions (1,2), reduced ability to kill or clear the trapped bacteria (4,17,22,24), and an exuberant neutrophilic inflammatory response which persists even if the stimulus is reduced and provides the agents of lung destruction in the form of proteolytic enzymes and oxidants (13,19).…”

Enhanced IgE allergic response to Aspergillus fumigatus in CFTR−/− mice

“…In addition, class I mutations that result in the production of nonfunctional CFTR protein have also been shown to cause aberrant inflammatory responses, characterized by increased levels of TNFa, KC, mip2 and infective inflammatory responses toward Pseudomonas bacterial clearance. 1 Ineffective and excessive inflammatory response to invading microbes in the CF airways seem to go beyond the effects of the CF mutation on the epithelial-bacterial interaction. This is evidenced by the data from CF infants, who despite having any detectable infection still produce elevated levels of proinflammatory cytokines.…”