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| Effect of 17-AAG combined with Caspofungin on invasive pulmonary aspergillosis in rats with neutrophil deficiency |
| ZHAN Xin1 WU Shiheng1 DENG Lin1 ZHANG Hongyue1 GAO Fusheng2▲ |
1.Clinical Medical School, Weifang Medical University, Shandong Province, Weifang 261000, China;
2.Department of Respiratory Medicine, Affiliated Hospital of Weifang Medical University, Shandong Province, Weifang 261000, China |
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Abstract Objective To explore the effects of the combination of Hsp90 inhibitor 17-AAG (17-allyl-17-demethoxygeldanamycin) and Caspofungin (CAS) in the treatmemt of invasive aspergillosis (IPA) with neutrophil deficiency. Methods Forty male Wistar rats were divided into 4 groups, group A, group B, group C and group D, according to random number table method, with 10 rats in each group. Neutrophil deficiency models were made by intraperitoneal injection of Cyclophosphamide in four groups of rats, and then Aspergillus fumigatus spore suspension was inhaled through nose. Group A was fed normally and served as blank control. Group B and C were given CAS of 1 mg/kg and 17-AAG of 1 mg/kg respectively by intraperitoneal injection. Group D was given 17-AAG combined with CAS (the same usage and dosage) for 10 days. The survival status of rats was recorded. The serum galactomannan antigen (GM) was detected on the 3rd and 7th day after treatment, and the lung tissues were stained with GMS to observe the fungal load at the infected sites. Results Compared with group A, the survival rates of group B and group D were significantly increased (P < 0.01), and the average survival time of group D was longer than that of group B, but the difference was not statistically significant (P > 0.05). Compared with group A, there was no significant difference in GM values between the groups on the third day of treatment (P > 0.05). On the 7th day of treatment, the GM values of each treatment group were lower than those of group A (P < 0.01), while group D was lower than group B (P < 0.05). GMS staining of lung slices showed that the lesions of fungal infection decreased in all treatment groups, and the most significant reduction was found in group D. No lesions were found on the 15th day of treatment. Conclusion 17-AAG improves the efficacy of CAS in the treatment of IPA by inhibiting stress response.
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[1] Chamilos G，Kontoyiannis DP. Update on antifungal drug resistance mechanisms of Aspergillus fumigatus [J]. Drug Resist Updat，2005，8（6）：344-358.
[2] Snelders E，Melchers WJ，Verweij PE. Azole resistance in Aspergillus fumigatus： a new challenge in the management of invasive aspergillosis [J]. Future Microbiol，2011， 6（3）：335-347.
[3] De Pauw B，Walsh TJ，Donnelly JP，et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group （EORTC/MSG） Consensus Group [J]. Clin Infect Dis，2008，46（12）：1813-1821.
[4] Patterson TF，Thompson GR，Denning DW，et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis：2016 Update by the Infectious Diseases Society of America [J]. Clin Infect Dis，2016，63（4）：1-60.
[5] Morrison VA. Echinocandin antifungals：review and update [J]. Expert Rev Anti Infect Ther，2006，4（2）：325-342.
[6] Maschmeyer G，Glasmacher A. Pharmacological properties and clinical efficacy of a recently licensed systemic antifungal，caspofungin [J]. Mycoses，2005，48（4）：227-234
[7] Cowen LE，Steinbach WJ. Stress，drugs，and evolution：the role of cellular signaling in fungal drug resistance [J]. Eukaryotic Cell，2008，7（5）：747-764.
[8] Cowen LE. The evolution of fungal drug resistance：modulating the trajectory from genotype to phenotype [J]. Nat Rev Microbiol，2008，6（3）：187-198.
[9] Leach MD，Klipp E，Cowen LE，et al. Fungal Hsp90：abiological transistor that tune scelular outputs to thermal inputs [J]. Nat Rev Microbiol，2012，10（10）：693-704.
[10] Mehrad B，Strieter RM，Standiford TJ. Role of TNF-α in pulmonary host defense in murine invasive Aspergillosis [J]. J Immunol，1999，162（3）：1633-1640.
[11] 王妍，龙飞，祁卉卉，等.烟曲霉菌孢子对哮喘大鼠气道炎症和气道反应性的影响[J].中国呼吸与危重监护杂志，2007，6（3）：185-190.
[12] Havaux X，Zeine A，Dits A，et al. A new mouse model of lung allergy induced by the spores of Alternaria alternate and Cladosporium herbarum molds [J]. Clin Exp Immunol，2004，139（2）：179-188.
[13] Denis O，van den Brule S，Heymans J，et al. Chronic intranasal administration of mould spores or extracts to unsensitized mice leads to lung allergic inflammation，hyperreactivity and remodeling [J]. Immunology，2007， 122（2）：268-278.
[14] Kontoyiannis DP，Marr KA，Park BJ，et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients，2001-2006：overview of the Transplant-Associated Infection Surveillance Network （TRANSNET） Database [J]. Clin Infect Dis，2010， 50（8）：1091-1100.
[15] Pappas PG，Alexander BD，Andes DR，et al. Invasive fungal infections among organ transplant recipients：results of the Transplant Associate Infection Surveillance Network （TRANSNET） [J]. Clin Infect Dis，2010，50（8）：1101-1111.
[16] Trepel J，Mollapour M，Giaccone G，et al. Targeting the dynamic HSP90 complex in cancer [J]. Nat Rev Cancer，2010，10（8）：537-549.
[17] Whitesell L，Lindquist SL. HSP90 and the chaperoning of cancer [J]. Nat Rev Cancer，2005，5（10）：761-772.
[18] Fortwendel JR，Juvvadi PR，Pinchai N，et al. Differential effects of inhibiting chitin and 1，3-{beta}-D-glucan synthesis in ras and calcineurin mutants of Aspergillus fumigatus [J]. Antimicrob Agents Chemother，2009，53（2）：476-482.
[19] Li J，Buchner J. Structure，function and regulation of the hsp90 machinery [J]. Biomed J，2013，36（3）：106-117.
[20] Li J，Soroka J，Buchner J. The Hsp90 chaperone machinery；conformational dynamics and regulation by cochaperones [J]. Acta Biochim Biophys Sin，2012，1823（3）：624-635. |
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