Therapeutic Effects of α1-Antitrypsin on Psedumonas aeruginosa Infection in ENaC Transgenic Mice.
Cystic fibrosis (CF) is a genetic disease with many airway pathological features, including aberrant epithelial sodium channel (ENaC) function, persistent Pseudomonas aeruginosa (PA) infection and neutrophil-dominant inflammation. PA infection in CF airways is difficult to treat due to antibiotic resistance and other factors. Recently, α1-antitrypsin (A1AT) have been shown to be effective to reduce CF airway PA infection. However, there is a dearth of studies about the mechanisms underlying A1AT's therapeutic effects. The goal of our study is to provide an animal model of A1AT therapy in CF lungs. ENaC transgenic mice with PA infection were used as a CF-like model. Mice were intratracheally treated with PA or saline (control) in a fibrin plug. Two hours after PA infection, aerosolized A1AT were delivered to mouse lungs once daily. At day 1 and day 3 post PA infection, lung inflammation, PA load as well as host defence protein short palate, lung, and nasal epithelium clone 1 (SPLUNC1) were measured. At day 1 post PA infection when A1AT was delivered once to ENaC transgenic mouse lungs, A1AT did not reduce lung inflammation (e.g., neutrophils) and PA load. However, at day 3 post PA infection when ENaC transgenic mice received three repeated A1AT treatments, a significant decrease in airspace inflammation and PA load was observed. Although A1AT prevented the loss of SPLUNC1 in bronchoalveolar lavage fluid of PA-infected wild-type mice, it did not restore SPLUNC1 levels in ENaC transgenic mice. Our current study has provided a valid and quick A1AT therapeutic model in CF-like lungs that may serve as a platform for future mechanistic studies about how A1AT exerts beneficial effects in human CF patients.
Department of Medicine, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America; Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
David P
DP
Nichols
Department of Medicine, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
Di
D
Jiang
Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
Carrie
C
Happoldt
Department of Medicine, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
Reena
R
Berman
Department of Medicine, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
Hong Wei
HW
Chu
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D000515:alpha 1-Antitrypsin / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D053503:Epithelial Sodium Channels; D000515:alpha 1-Antitrypsin