Administration of nonviral gene vector encoding rat beta-defensin-2 ameliorates chronic Pseudomonas aeruginosa lung infection in rats.
BACKGROUND
Beta-defensin-2 (BD-2) plays an important role in host defense against pathogenic microbe challenge by its direct antimicrobial activity and immunomodulatory functions. The present study aimed to determine whether genetic up-regulation of rat BD-2 (rBD-2) could ameliorate chronic Pseudomonas aeruginosa lung infection in rats.


METHODS
Plasmid-encoding rBD-2 was delivered to lungs in vivo using linear polyethylenimine at 48 h before challenging with seaweed alginate beads containing P. aeruginosa. Macroscopic and histopathological changes of the lungs, bacterial loads, inflammatory infiltration, and the levels of cytokines/chemokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, kertinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2)] were measured at 3 and 7 days post-infection (p.i.).


RESULTS
The overexpression of rBD-2 resulted in a significant increase in animal survival rate (at 3 days p.i.), a significant decrease in bacterial loads in the lungs (at 3 and 7 days p.i.), and significantly milder lung pathology. In addition, the overexpression of rBD-2 led to increased infiltration of polymorphonuclear neutrophils (PMN), and elevated protein expression of cytokines/chemokines (IL-1beta, TNF-alpha, KC and MIP-2) at the early stage of infection (at 3 days p.i.), at the same time as being dramatically decreased at the later stage of infection (at 7 days p.i.).


CONCLUSIONS
Genetic up-regulation of rBD-2 increased animal survival rate, and reduced bacterial loads in lungs after bacterial infection. The overexpression of rBD-2 also modulated the production of several cytokines/chemokines and increased PMN recruitment at the early stage of infection. Our findings indicate that the enhancement of BD-2 may be an efficacious intervention for chronic P. aeruginosa lung infection.
Department of Respiratory Medicine, Tongji Hospital, Key Laboratory of Pulmonary Diseases of Ministry of Health of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, China.
Qiongjie
Q
Hu
Peng
P
Zuo
Bing
B
Shao
Shuo
S
Yang
Guopeng
G
Xu
Fen
F
Lan
Xiaoxia
X
Lu
Weining
W
Xiong
Yongjian
Y
Xu
Shengdao
S
Xiong
D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011552:Pseudomonas Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011550:Pseudomonas aeruginosa; D051381:Rats; D017207:Rats, Sprague-Dawley; D023083:beta-Defensins / Q000235:genetics*
D018925:Chemokines; D016207:Cytokines; D023083:beta-Defensins; C549474:beta-defensin-2, rat