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

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

“…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).…”

IL-10 delivery by AAV5 vector attenuates inflammation in mice with pseudomonas pneumonia

“…2,3 Supporting this theory are studies of chronic P. aeruginosa infection in IL-10T and CFTR knockout mice, demonstrating dramatic weight loss, greater polymorphonuclear neutrophil infiltration and higher concentrations of proinflammatory cytokines following infection compared with wild-type mice. [19][20][21][22][23][24] In this study, we carried out intratracheal inoculation with AAV5.Cb-mIL10 6 weeks before infection using a chronic P. aeruginosa model in IL-10T mice. IL-10 was expressed in the alveoli and produced at significantly higher levels in the epithelial lining fluid and lung homogenate in vector-treated mice compared with mice that received PBS.…”

“…It is important to note that there are strong similarities between the IL-10T and CFTR knockout mice in response to both chronic and acute P. aeruginosa lung infections. This response is characterized by greater neutrophil recruitment, more severe weight loss and increased areas of lung inflammation when compared with wild-type mice, [19][20][21][22][23][24]26 suggesting an important role for IL-10 in regulating the inflammatory response to P. aeruginosa. As the IL-10T mice were created by a targeted mutation of the IL-10 gene, the result is a dramatic deficiency in, but not elimination of, IL-10 production.…”

“…[19][20][21] These findings are similar to those of P. aeruginosainfected CF mice. [21][22][23][24] IL-10T mice repeatedly exposed to mucoid P. aeruginosa have higher mortality rates and more severe lung pathology when compared with C57BL/6 controls similarly infected; 25 in addition, IL-10T mice have a prolonged inflammatory response to acute P. aeruginosa challenge. 26 Research shows that treatment with IL-10 reduces neutrophil and leukocyte recruitment, decreases proinflammatory cytokine production, and causes an increase in weight loss and tissue injury in the airways of sensitized animals following antigen exposure or P. aeruginosa challenge, 19,21,[27][28][29][30] supporting the use of IL-10 in ameliorating inflammation.…”

Strain-dependent pulmonary gene expression profiles of a cystic fibrosis mouse model

“…The gene expression profiles and cell type staining measured here indicate, at least in part, a contributing difference in immune response, cell proliferation, and lymphocyte activation to the lung phenotype. The genetic factors influencing the strainspecific adaptation or repair response may be important CF lung modifiers, perhaps mechanistically linked to the CF lung modifier gene transforming growth factor (TGF)␤ (4) and, furthermore, may have functional consequences in the established exaggerated inflammatory response of CF mice to Staphylococcus aureus (2) and P. aeruginosa exposure (31), which, in the latter case, has been shown to be independent of Cftr mutation genotype. The pulmonary phenotypes presented may also have been influenced by an undetected pathogen, but such a finding would not alter the observation of strain-specific CF lung responses.…”