The blood clotting dysfunction and therapeutic efect of low molecular hepa~n in a mouse model of invasive pulmonary aspergillosi_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

RONG Ling ,  ZHOU Xin , LI Feng , HE Mudan

Department of Respiratory Medicine，Shanghai First People’s Hospital，Shanghai Jiaotong University．Shanghai，200080，China Corresponding author：ZHOU Xin，E-mail：xzhou53@163.con;

Corresponding author：

ZHOU Xin, Email: xzhou53@163.com

Keywords：

Invasive pulmonary aspergillosis; Blood clotting function; Low molecular hepafin; Disseminated intravascular coagulatio

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Objective To investigate the blood clotting dysfunction of invasive pulmonary aspergillosis(IPA)and the therapeutic effect of low molecular hepafin in a mouse model．Methods The neutropenic IPA mouse model was constructed by being given cyclophosphamide to depress immunologic function，and then intranasally challenged with Aspergillus fumigatus conidia．(1)Blood clotting function were assessed by bleeding time，clotting time，platelet count and antithrombase-III(AT-III)activity．Seventy-two mice were randomly assigned into 4 groups．Group A received only normal saline．group B received normal saline to substitute the cycloph0sphamide，and the rest equal to group D．Group C received normal saline to substitute the AspergiUus fumigatus conidia suspension，and the rest equal to group D．Group D(model group)received cyclophosphamide(intraperitoneally，150 mg／kg，d4，d1)and Aspergillus fumigatus conidia suspension(intranasally，40 μL／mouse，1．5×10∧5／mL，d0)．Six mice were randomly sacrificed in each group for analysis of blood clotting function per 24 h after inoculation for 3 times．(2)Therapeutic effect of low molecular heparin was determined by survival time of IPA mice．One hundred and eighteen mice were randomly assigned into 4 groups after challenged with 6×10 conidia／mouse and received one of the following regimens daily from dl to d7 after challenge，vehicle(group E，n=29)，low molecular heparin(group F，n=30，subcutaneous injection，1000 IU／kg，qd×7 d)，amphotericin B(group G，n=29，intraperitoneal，1 m kg，qd×7 d)，low molecular heparin plus amphotericin B(group H，n=30)．Mice survivals were recorded once daily to d21 after innoculation．Results (1)AT-III activity of group D decreased significantly 24 h after innoculation．Bleeding time and clotting time decreased significantly and AT—III activity decreased sequentially 48 h after innoculation．The platelet decreased significantly 72 h after innoculation，and bleeding time shoaened further．Clotting time was longer than that 0f 48 h．but still shorter than norm al and AT-III activity decreased sequentially．There were significant differences when comparing group D with group A，B and C(all P lt;0.01)．And there was no significant difference between group A，B and C(all P gt;0．05)．(2)Survival analysis indicated that the therapeutic effect of low molecular hepafin plus amphotericin B was better than that of amphotericin B or low molecular heparin alone．No therapeutic effect was found in group F(group E vs group F，P gt;0．05，both group E and group F compared with group H，P lt;0．01．Group H vs group G，P lt;0．05．Both group E and group F compared with group G，P lt;0．05)．Conclusions The results suggest that there is blood clotting dysfunction in IPA mice and AT—III activity may be an early index to monitor the disfunction．Compared with the therapeutic effect of amphoterinein B alone，low molecular hepafin plus amphoterincin B can prolong survival of neutropenic IPA mice

Citation： RONG Ling,ZHOU Xin,LI Feng,HE Mudan. The blood clotting dysfunction and therapeutic efect of low molecular hepa~n in a mouse model of invasive pulmonary aspergillosi. Chinese Journal of Respiratory and Critical Care Medicine, 2008, 08(6): 440-444. doi: Copy

1.	张宝才肺真菌病．中国呼吸与危重监护杂志，2003，2：319-320.
2.	Lin SJ，Sehranz J，Teutsch SM．Aspergillosis case-fatality rate：systematic review of the literature．Clin Infeet Dis，2001，32：358-366.
3.	NCCLS．Reference method for broth dilution antifungal susceptibility testing of filamentous fungi；approved standard．NCCLS document M-38A．NCCLS，2002，18：1-29.
4.	荣令，周新．侵袭性肺曲霉病发病机制研究进展．中国呼吸与危重监护杂志，2008，7：152-155.
5.	Kamai Y，Chiang LY，Lopes Bezerra LM，et al．Interactions of Aspergillus fumigatus with vascular endothelial cells．Med Mycol，2006， 44：S115-Sl17.
6.	Lopes Bezerra LM，Filler SG．Interactions of Aspergillus fumigatus with endothelial cells：internalization，injury，and stimulation of tissue factor activity．Blood，2004，103：2143-2149.
7.	Becker MJ，De Marie S，Fens MH，et a1．Pathophysiology of unilateral pulmonary aspergillosis in an experimental rat mode1．Med Mycol， 2006，44：133-139.
8.	Lai CC，Liaw SJ，Lee LN，et al．Invasive pulmonary aspergillosis： high incidence of disseminated intravaseular coagulation in fatal cases．J Mierobiol Immunol Infect，2007，40：141-147. 9 张国材．弥散性血管内凝血的实验室检查及其临床价值．新医学，2007，38：269-272.
9.	Kaufman HF，Tomee JF．Defense mechanisms of the airways against Aspergillus fumigatus：role in invasive aspergillosis．Chem Immunol， 2002，81：94-113.
10.	Vignoli A，Marchetti M，Balducci D，et al．Diferential efect of the lowmolecular- weight heparin，daheparin，and unfraetionated heparin on mierovascular endothelial cell hemostatie properties．Haematologica，2006， 91：207-214.
11.	唐邦清，黄大明，黄晖，等．低分子肝素早期干预预防感染性休克并发弥散性血管内凝血．临床荟萃，2005，20：281-282.
12.	Asakura H，Sano Y，Yoshida T，et al．Beneficial effect of low-molecular—weight heparin against 1ip0p0lysaccharide-induced disseminated intravascular coagulation in rats is abolished by coadministration of tran examie acid．Intensive Care Med，2004，30：1950-1955.
13.	Miyake Y，Yokota K，Fujishima Y，et al．The effects of danaparoid， dalteparin and heparin on tissue factor-induced experimental dissem inated intravaseular coagulation and bleeding time in the rat．Blood Coagul Fibrinolysis，2001，12：349-357.
14.	侯百东，潘家绮，范连凯，等．急性弥散性血管内凝血65例临床分析．中华医学杂志，2001，81：752-753.
15.	S10fstm SH，vail’t Veer C，Buurnmn WA，et al．Low molecular weight heparln attenuates multiple organ failure in a murine model of disseminated intravaseular coagulation．Crit Care Med，2005，33：1365-1370．.

1. 张宝才肺真菌病．中国呼吸与危重监护杂志，2003，2：319-320.
2. Lin SJ，Sehranz J，Teutsch SM．Aspergillosis case-fatality rate：systematic review of the literature．Clin Infeet Dis，2001，32：358-366.
3. NCCLS．Reference method for broth dilution antifungal susceptibility testing of filamentous fungi；approved standard．NCCLS document M-38A．NCCLS，2002，18：1-29.
4. 荣令，周新．侵袭性肺曲霉病发病机制研究进展．中国呼吸与危重监护杂志，2008，7：152-155.
5. Kamai Y，Chiang LY，Lopes Bezerra LM，et al．Interactions of Aspergillus fumigatus with vascular endothelial cells．Med Mycol，2006， 44：S115-Sl17.
6. Lopes Bezerra LM，Filler SG．Interactions of Aspergillus fumigatus with endothelial cells：internalization，injury，and stimulation of tissue factor activity．Blood，2004，103：2143-2149.
7. Becker MJ，De Marie S，Fens MH，et a1．Pathophysiology of unilateral pulmonary aspergillosis in an experimental rat mode1．Med Mycol， 2006，44：133-139.
8. Lai CC，Liaw SJ，Lee LN，et al．Invasive pulmonary aspergillosis： high incidence of disseminated intravaseular coagulation in fatal cases．J Mierobiol Immunol Infect，2007，40：141-147. 9 张国材．弥散性血管内凝血的实验室检查及其临床价值．新医学，2007，38：269-272.
9. Kaufman HF，Tomee JF．Defense mechanisms of the airways against Aspergillus fumigatus：role in invasive aspergillosis．Chem Immunol， 2002，81：94-113.
10. Vignoli A，Marchetti M，Balducci D，et al．Diferential efect of the lowmolecular- weight heparin，daheparin，and unfraetionated heparin on mierovascular endothelial cell hemostatie properties．Haematologica，2006， 91：207-214.
11. 唐邦清，黄大明，黄晖，等．低分子肝素早期干预预防感染性休克并发弥散性血管内凝血．临床荟萃，2005，20：281-282.
12. Asakura H，Sano Y，Yoshida T，et al．Beneficial effect of low-molecular—weight heparin against 1ip0p0lysaccharide-induced disseminated intravascular coagulation in rats is abolished by coadministration of tran examie acid．Intensive Care Med，2004，30：1950-1955.
13. Miyake Y，Yokota K，Fujishima Y，et al．The effects of danaparoid， dalteparin and heparin on tissue factor-induced experimental dissem inated intravaseular coagulation and bleeding time in the rat．Blood Coagul Fibrinolysis，2001，12：349-357.
14. 侯百东，潘家绮，范连凯，等．急性弥散性血管内凝血65例临床分析．中华医学杂志，2001，81：752-753.
15. S10fstm SH，vail’t Veer C，Buurnmn WA，et al．Low molecular weight heparln attenuates multiple organ failure in a murine model of disseminated intravaseular coagulation．Crit Care Med，2005，33：1365-1370．.

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Chinese Journal of Respiratory and Critical Care Medicine

The blood clotting dysfunction and therapeutic efect of low molecular hepa~n in a mouse model of invasive pulmonary aspergillosi

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