Alleviation of renal and pulmonary injury by immunomodulation in leptospirosis: hamster model.
OBJECTIVE
Severe leptospirosis manifestations include acute renal failure, caused by acute interstitial nephritis and pulmonary hemorrohage. Spirochete invasion and toxicity of outer membrane cause robust inflammatory host responses. These responses lead to the generation of cytokines, chemokines, and inflammatory cell infiltrations which result in severe organ dysfunctions. The immunomodulation by the modulation of host immune response may alleviate the renal and pulmonary injury. The authors determined whether the current immunosuppressive agents could alleviate the inflammation and minimize the organ injury in hamster model.


METHODS
The animal experiments were conducted with the approval of The Ethical Research Committee of Chulalongkorn University Hospital. The leptospira interrogan serovar pyrogenese was isolated from a wild rat. The spirochete was grown in Fletcher's semisolid media and after subcultures were transferred to the Fletcher's liquid media. An amount of 0.5 ml of the spirochete culture media containing 1 x 10(8) leptospires/ml was intraperitoneally injected to golden Syrian hamsters (Mesocrietus auratus), age 4-6 weeks, weighing 60-80 grams. The hamsters were randomed into 5 groups (n = 4 in each group) namely, 1) Normal group (Control group), 2) Leptospira group, 3) CsA group (leptospira with cyclosporine feeding, 100 mg/kg/ day), 4) Rapa group (leptospira with rapamicin feeding, 0.6 mg/kg/day), and 5) Irra group (leptospira with irradiation). Cyclosporine and rapamicin were started at day 0 after the spirochete injection. Gamma ray dose 200 cGy was irradiated to the hamster 3 days before the spirochete inoculation. The animals were autopsied or euthanized if expired or at day 5 post inoculation. The blood samples for BUN, and creatinine were drawn before the inoculation and at autopsy or euthanasia.


RESULTS
The inoculation of L Interrogan 0.5 ml (1 x 10(8) leptospires/ml) without immunomodulation cause mortality of all animals at day 4 or day 5 post inoculation. The blood chemistry showed acute severe azotemia. The autopsy findings revealed severe interstitial nephritis and severe pulmonary hemorrhage. The hamsters in the Rapa group had only minimal pulmonary hemorrhage and minimal focal interstitial inflammation of kidney. There were cytoadherance of inflammatory cells to the endothelial cells in lungs and kidneys without the intrusion into the interstitium. The blood chemistry in Rapa group showed mild elevation of BUN and Cr. The immunomodulation by cyclosporine and irradiation did not alleviate the disease. On the contrary, cyclosporine and irradiation caused more severe histopathology.


CONCLUSIONS
The immunomodulation by rapamicin in leptospirosis in hamsters could alleviate the kidney and pulmonary injuries. The up-regulation of IL-2 in peripheral blood lymphocytes did not result in the kidney and pulmonary injuries.
Praditpornsilpa
Kearkiat
K
Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University Hospital, Bangkok, Thailand. kearkiat@hotmail.com
Sangjun
Noppadon
N
Kittikowit
Wipawee
W
Phulsuksombati
Duangporn
D
Avihingsanon
Yingyos
Y
Kansanabuch
Talerngsak
T
Tungsanga
Kriang
K
Eiam-Ong
Somchai
S
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology*; D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007668:Kidney / Q000473:pathology*; D007919:Leptospira; D007922:Leptospirosis / Q000150:complications* / Q000188:drug therapy*; D008168:Lung / Q000473:pathology*; D020123:Sirolimus / Q000008:administration & dosage*
D007166:Immunosuppressive Agents; D020123:Sirolimus