摘要：

The discovery of the CFTR gene in 1989 has lead to rapid progress in understanding the molecular basis of cystic fibrosis (CF) and the biological properties of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. However, more than 10 years later, recurrent lung infections with Pseudomonas aeruginosa, which lead to chronic lung disease and eventual respiratory failure, remain the major cause of morbidity and mortality among CF patients. A distinguishing feature of lung disease in CF is an exaggerated and persistent inflammatory response, characterized by the accumulation of excessive numbers of neutrophils and dysregulated cytokine production. The events leading to the establishment of lung infection with P. aeruginosa, especially the inflammatory and immunological events, and the relation between the CF defect and infection, remain largely undefined. Progress in this area has been hampered by the lack of a suitable animal model. An exciting achievement in the past few years has been the development of a number of variants of CFTR -deficient mice which exhibit defective cAMP-mediated Cl conductance and have a range of clinical phenotypes from mild to severe. In parallel, a model of chronic P. aeruginosa lung infection has been established in genetically and immunologically well-defined inbred mouse strains which differ in susceptibility to this infection in the lung. BALB/c mice are resistant, while DBA/2 mice are extremely susceptible, with high mortality within 3 days of infection. C57BL/6 and A/J mice are relatively susceptible and experience low mortality. Furthermore, the bacterial load correlates with the magnitude and quality of the inflammatory response in the infected lungs of BALB/c and C57BL/6 mice. Although results of infection studies in CFTR -deficient mice have been variable, C57BL/6- Cftrm1UNC/Cftrm1UNC knockout mice compared to littermate control mice are highly susceptible to chronic P. aeruginosa infection in the lung. The availability of CFTR knockout mice and non-CF inbred mice differing in susceptibility to chronic P. aeruginosa infection offers useful tools for progress in understanding the genesis of chronic P. aeruginosa infection and the ensuing inflammation in the CF lung, as well as the relation between the CF defect and infection. Information generated from these studies will provide the rationale for the development of novel immunomodulatory measures capable of ameliorating or modulating the chronic inflammation associated with CF lung disease. Pediatr Pulmonol. 2000;30:413–424. 2000 Wiley-Liss, Inc.

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