• 上海交通大學(xué)附屬第一人民醫(yī)院呼吸科（上海 200080）;

曲霉在自然界中廣泛分布，約20種曲霉能感染人類和動(dòng)物，其中最常見的有煙曲霉、黃曲霉、土曲霉和黑曲霉等。曲霉孢子在空氣中傳播，人吸入后曲霉可以在氣道內(nèi)定植、致敏、感染，當(dāng)人體免疫功能低下時(shí)可產(chǎn)生危及生命的侵襲性肺曲霉?。↖PA）。近年來IPA發(fā)病率呈上升趨勢(shì)，已成為僅次于念珠菌病的主要肺部真菌感染性疾病[1]。雖然IPA已成為器官移植受者、惡性血液病和惡性腫瘤患者等高危人群的重要死因，但對(duì)其發(fā)病機(jī)制了解甚少。本文著重論述近年來IPA發(fā)病機(jī)制的研究進(jìn)展。

引用本文： 榮令,周新. 侵襲性肺曲霉病發(fā)病機(jī)制研究進(jìn)展. 中國(guó)呼吸與危重監(jiān)護(hù)雜志, 2008, 08(2): 152-155. doi: 復(fù)制

1. 張寶才.肺真菌病.中國(guó)呼吸與危重監(jiān)護(hù)雜志,2003,2:319-320.
2. Nierman WC,Pain A,Anderson MJ,et al.Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus.Nature,2005,438:1151-1156.
3. Rementeria A,López-Molina N,et al.Genes and molecules involved in Aspergillus fumigatus virulence.Rev Iberoam Micol.2005,22:1-23.
4. Brakhage AA.Systemic fungal infections caused by Aspergillus species: epidemiology, infection process and virulence determinants.Curr Drug Targets,2005,6:875-886.
5. Lessing F,Kniemeyer O,Wozniok I,et al.The Aspergillus fumigatus transcriptional regulator AfYap1 represents the major regulator for defense against reactive oxygen intermediates but is dispensable for pathogenicity in an intranasal mouse infection model.Eukaryot Cell,2007,6:2290-2302.
6. Lamarre C,Ibrahim-Granet O,Du C,et al.Characterization of the SKN7 ortholog of Aspergillus fumigatus.Fungal Genet Biol,2007,44:682-690.
7. Kupfahl C,Heinekamp T, Geginat G,et al.Deletion of the gliP gene of Aspergillus fumigatus results in loss of gliotoxin production but has no effect on virulence of the fungus in a low-dose mouse infection model.Mol Microbiol,2006,62:292-302.
8. Cramer RA Jr,Gamcsik MP,Brooking RM,et al.Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production.Eukaryot Cell,2006 ,5:972-980.
9. Sugui JA,Pardo J,Chang YC,et al.Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone.Eukaryot Cell,2007,6:1562-1569.
10. Schrettl M,Bignell E, Kragl C,et al.Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection.PLoS Pathog,2007,3:1195-1207.
11. Ibrahim-Granet O,Dubourdeau M,Latge JP,et al.Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis.Cell Microbiol,2008,10:134-148.
12. Zhuo H,Hu H,Zhang L,et al.Protein O-mannosyltransferase 1 (AfPmt1p) in Aspergillus fumigatus is crucial for cell wall integrity and conidia morphology especially at an elevated temperature.Eukaryot Cell,2007,Epub ahead of print.
13. García ME,Caballero J,Blanco I,et al.Changes in the elastase activity and colonization ability of Aspergillus fumigatus after successive inoculations in mice.Rev Iberoam Micol,2006,23:221-223.
14. Filler SG,Sheppard DC.Fungal invasion of normally non-phagocytic host cells.PLoS Pathog.2006,2:e129.
15. Vogl G,Lesiak I,Jensen DB,et al.Immune evasion by acquisition of complement inhibitors: the mould Aspergillus binds both factor H and C4b binding protein.Mol Immunol,2008,45:1485-1493.
16. Volling K,Brakhage AA,Saluz HP.Apoptosis inhibition of alveolar macrophages upon interaction with conidia of Aspergillus fumigatus.FEMS Microbiol Lett,2007,275:250-254.
17. Kauffman HF,Tomee JF.Defense mechanisms of the airways against Aspergillus fumigatus: role in invasive aspergillosis.Chem Immunol,2002,81:94-113.
18. Zarember KA,Sugui JA,Chang YC,et al.Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion.J Immunol,2007,178:6367-6373.
19. Bellocchio S,Montagnoli C,Bozza S,et al.The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo.J Immunol,2004,172:3059-3069.
20. Phadke AP,Akangire G,Park SJ,et al.The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis.Am J Respir Crit Care Med,2007,175:1165-1172.
21. Gafa V,Remoli ME,Giacomini E,et al.In vitro infection of human dendritic cells by Aspergillus fumigatus conidia triggers the secretion of chemokines for neutrophil and Th1 lymphocyte recruitment.Microbes Infect,2007,9:971-980.
22. Serrano-Gómez D,Leal JA,Corbí AL.DC-SIGN mediates the binding of Aspergillus fumigatus and keratinophylic fungi by human dendritic cells.Immunobiology,2005,210:175-183.
23. Steele C,Rapaka RR,Metz A,et al.The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus.PLoS Pathog,2005,1:e42.
24. Dubourdeau M,Athman R,Balloy V,et al.Aspergillus fumigatus induces innate immune responses in alveolar macrophages through the MAPK pathway independently of TLR2 and TLR4.J Immunol,2006,177:3994-4001.
25. Sainz J,Hassan L,Perez E,et al.Interleukin-10 promoter polymorphism as risk factor to develop invasive pulmonary aspergillosis.Immunol Lett,2007,109:76-82.
26. Seo KW,Kim DH,Sohn SK,et al.Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation.Bone Marrow Transplant,2005,6:1089-1095.
27. Sainz J,Pérez E,Hassan L,et al.Variable number of tandem repeats of TNF receptor type 2 promoter as genetic biomarker of susceptibility to develop invasive pulmonary aspergillosis.Hum Immunol,2007,68:41-50.
28. Mezger M,Steffens M,Beyer M,et al.Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. Blood.2008,111:534-536.
29. Kamai Y,Chiang LY,Lopes Bezerra LM,et al.Interactions of Aspergillus fumigatus with vascular endothelial cells.Med Mycol,2006,44,:S115-117.
30. 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.
31. Lai CC,Liaw SJ,Lee LN,et al.Invasive pulmonary aspergillosis: high incidence of disseminated intravascular coagulation in fatal cases.J Microbiol Immunol Infect,2007,40:141-147.
32. Balloy V,Huerre M,Latgé JP,et al.Differences in patterns of infection and inflammation for corticosteroid treatment and chemotherapy in experimental invasive pulmonary aspergillosis.Infect Immun,2005,73:494-503.
33. Rodrigues AG,Araujo R,Pina-Vaz C.Human albumin promotes germination, hyphal growth and antifungal resistance by Aspergillus fumigatus.Med Mycol,2005,43:711-717.
  1. 1. 張寶才.肺真菌病.中國(guó)呼吸與危重監(jiān)護(hù)雜志,2003,2:319-320.
  2. 2. Nierman WC,Pain A,Anderson MJ,et al.Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus.Nature,2005,438:1151-1156.
  3. 3. Rementeria A,López-Molina N,et al.Genes and molecules involved in Aspergillus fumigatus virulence.Rev Iberoam Micol.2005,22:1-23.
  4. 4. Brakhage AA.Systemic fungal infections caused by Aspergillus species: epidemiology, infection process and virulence determinants.Curr Drug Targets,2005,6:875-886.
  5. 5. Lessing F,Kniemeyer O,Wozniok I,et al.The Aspergillus fumigatus transcriptional regulator AfYap1 represents the major regulator for defense against reactive oxygen intermediates but is dispensable for pathogenicity in an intranasal mouse infection model.Eukaryot Cell,2007,6:2290-2302.
  6. 6. Lamarre C,Ibrahim-Granet O,Du C,et al.Characterization of the SKN7 ortholog of Aspergillus fumigatus.Fungal Genet Biol,2007,44:682-690.
  7. 7. Kupfahl C,Heinekamp T, Geginat G,et al.Deletion of the gliP gene of Aspergillus fumigatus results in loss of gliotoxin production but has no effect on virulence of the fungus in a low-dose mouse infection model.Mol Microbiol,2006,62:292-302.
  8. 8. Cramer RA Jr,Gamcsik MP,Brooking RM,et al.Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production.Eukaryot Cell,2006 ,5:972-980.
  9. 9. Sugui JA,Pardo J,Chang YC,et al.Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone.Eukaryot Cell,2007,6:1562-1569.
  10. 10. Schrettl M,Bignell E, Kragl C,et al.Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection.PLoS Pathog,2007,3:1195-1207.
  11. 11. Ibrahim-Granet O,Dubourdeau M,Latge JP,et al.Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis.Cell Microbiol,2008,10:134-148.
  12. 12. Zhuo H,Hu H,Zhang L,et al.Protein O-mannosyltransferase 1 (AfPmt1p) in Aspergillus fumigatus is crucial for cell wall integrity and conidia morphology especially at an elevated temperature.Eukaryot Cell,2007,Epub ahead of print.
  13. 13. García ME,Caballero J,Blanco I,et al.Changes in the elastase activity and colonization ability of Aspergillus fumigatus after successive inoculations in mice.Rev Iberoam Micol,2006,23:221-223.
  14. 14. Filler SG,Sheppard DC.Fungal invasion of normally non-phagocytic host cells.PLoS Pathog.2006,2:e129.
  15. 15. Vogl G,Lesiak I,Jensen DB,et al.Immune evasion by acquisition of complement inhibitors: the mould Aspergillus binds both factor H and C4b binding protein.Mol Immunol,2008,45:1485-1493.
  16. 16. Volling K,Brakhage AA,Saluz HP.Apoptosis inhibition of alveolar macrophages upon interaction with conidia of Aspergillus fumigatus.FEMS Microbiol Lett,2007,275:250-254.
  17. 17. Kauffman HF,Tomee JF.Defense mechanisms of the airways against Aspergillus fumigatus: role in invasive aspergillosis.Chem Immunol,2002,81:94-113.
  18. 18. Zarember KA,Sugui JA,Chang YC,et al.Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion.J Immunol,2007,178:6367-6373.
  19. 19. Bellocchio S,Montagnoli C,Bozza S,et al.The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo.J Immunol,2004,172:3059-3069.
  20. 20. Phadke AP,Akangire G,Park SJ,et al.The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis.Am J Respir Crit Care Med,2007,175:1165-1172.
  21. 21. Gafa V,Remoli ME,Giacomini E,et al.In vitro infection of human dendritic cells by Aspergillus fumigatus conidia triggers the secretion of chemokines for neutrophil and Th1 lymphocyte recruitment.Microbes Infect,2007,9:971-980.
  22. 22. Serrano-Gómez D,Leal JA,Corbí AL.DC-SIGN mediates the binding of Aspergillus fumigatus and keratinophylic fungi by human dendritic cells.Immunobiology,2005,210:175-183.
  23. 23. Steele C,Rapaka RR,Metz A,et al.The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus.PLoS Pathog,2005,1:e42.
  24. 24. Dubourdeau M,Athman R,Balloy V,et al.Aspergillus fumigatus induces innate immune responses in alveolar macrophages through the MAPK pathway independently of TLR2 and TLR4.J Immunol,2006,177:3994-4001.
  25. 25. Sainz J,Hassan L,Perez E,et al.Interleukin-10 promoter polymorphism as risk factor to develop invasive pulmonary aspergillosis.Immunol Lett,2007,109:76-82.
  26. 26. Seo KW,Kim DH,Sohn SK,et al.Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation.Bone Marrow Transplant,2005,6:1089-1095.
  27. 27. Sainz J,Pérez E,Hassan L,et al.Variable number of tandem repeats of TNF receptor type 2 promoter as genetic biomarker of susceptibility to develop invasive pulmonary aspergillosis.Hum Immunol,2007,68:41-50.
  28. 28. Mezger M,Steffens M,Beyer M,et al.Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. Blood.2008,111:534-536.
  29. 29. Kamai Y,Chiang LY,Lopes Bezerra LM,et al.Interactions of Aspergillus fumigatus with vascular endothelial cells.Med Mycol,2006,44,:S115-117.
  30. 30. 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.
  31. 31. Lai CC,Liaw SJ,Lee LN,et al.Invasive pulmonary aspergillosis: high incidence of disseminated intravascular coagulation in fatal cases.J Microbiol Immunol Infect,2007,40:141-147.
  32. 32. Balloy V,Huerre M,Latgé JP,et al.Differences in patterns of infection and inflammation for corticosteroid treatment and chemotherapy in experimental invasive pulmonary aspergillosis.Infect Immun,2005,73:494-503.
  33. 33. Rodrigues AG,Araujo R,Pina-Vaz C.Human albumin promotes germination, hyphal growth and antifungal resistance by Aspergillus fumigatus.Med Mycol,2005,43:711-717.