Age influence on mice lung tissue response to Aspergillus fumigatus chronic exposure
More details
Hide details
Institute of Agricultural Medicine, Lublin, Poland
Department of Pathology and Diagnostic, Section of Pathological Anatomy, University of Verona, Verona, Italy
Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium
Department of Pneumonology, Oncology and Allergology, Medical University, Lublin, Poland
Department of Internal Medicine II, Clinical Division of Pulmonary Medicine, Medical University of Vienna, Vienna, Austria
Ann Agric Environ Med. 2015;22(1):69–75
Introduction and objective:
Exposure to conidia of Aspergillus fumigatus was described as a causative factor of a number of the respiratory system diseases, including asthma, chronic eosinophilic pneumonia, hypersensitivity pneumonitis and bronchopulmonary aspergillosis. The study investigates the effects of the repeated exposure to A. fumigatus in mice pulmonary compartment. Our work tackles two, so far insufficiently addressed, important aspects of interaction between affected organism and A. fumigatus: 1) recurrent character of exposure (characteristic for pathomechanism of the abovementioned disease states) and 2) impact of aging, potentially important for the differentiation response to an antigen.

Material and Methods:
In order to dissect alterations of the immune system involved with both aging and chronic exposure to A. fumigatus, we used 3- and 18-month-old C57BL/6J mice exposed to repeated A. fumigatus inhalations for 7 and 28 days. Changes in lung tissue were monitored by histological and biochemical evaluation. Concentration of pro- and anti-inflammatory cytokines in lung homogenates was assessed by ELISA tests.

Results and conclusions:
Our study demonstrated that chronic inflammation in pulmonary compartment, characterized by the significant increase of proinflammatory cytokines (IL1, IL6, IL10) levels, was the dominant feature of mice response to repeated A. fumigatus inhalations. The pattern of cytokines’ profile in the course of exposure was similar in both age groups, however in old mice the growth of the cytokines’ levels was more pronounced (especially in case of IL1).

This study was supported by the Polish Ministry of Science and Higher Education, IMW Statutory Project No. 13030: ‘The age influence on the immune response during remodeling of the bronchial tree induced in mice strain C57BL/6J by Aspergillus fumigatus’, and by European Union FP7 Health Research Grant No. HEALTH-F4–2008–202047: ‘Resolve chronic inflammation and achieve healthy ageing by understanding non-regenerative repair’.
Porter P, Susarla SC, Polikepahad S, Qian Y, Hampton J, Kiss A, Vaidya S, Sur S, Ongeri V, Yang T, Delclos GL, Abramson S, Kheradmand F, Corry DB. Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi. Mucosal Immunol. 2009; 2: 504–517.
Denning DW, O’Driscoll BR, Hogaboam CM, Bowyer P, Niven RM. The link between fungi and severe asthma: a summary of the evidence. Eur Respir J. 2006; 27: 615–626.
Park SJ, Mehrad B. Innate immunity to Aspergillus species. Clin Microbiol Rev. 2009; 22: 535–551.
Hohl TM, Rivera A, Pamer EG. Immunity to fungi. Curr Opin Immunol. 2006; 18: 465–472.
Phadke AP, Mehrad B. Cytokines in host defense against Aspergillus: recent advances. Med Mycol. 2005; 43(Supl 1): 173–176.
De Repentigny L, Petitbois S, Boushira M, Michaliszyn E, Senechal S, Gendron N, Montplaisir S. Acquired immunity in experimental murine aspergillosis is mediated by macrophages. Infect Immun. 1993; 61: 3791–3802.
Djeu JY. Modulators of immune responses to fungi. In: Murphy JW, Friedman H, Bendinelli M (eds.). Fungal infections and immune responses. New York, Plenum Press, 1993.p.521–532.
Murdock BJ, Shreiner AB, McDonald RA, Osterholzer JJ, White ES, Toews GB, Huffnagle GB. Coevolution of TH1, TH2, and TH17 responses during repeated pulmonary exposure to Aspergillus fumigatus conidia. Infect Immun. 2011; 79(1): 125–135.
Loeffler J, Haddad Z, Bonin M, Romeike N, Mezger M, Schumacher U, Kapp M, Gebhardt F, Grigoleit GU, Stevanovic S, Einsele H, Hebart H. Interaction analyses of human monocytes cocultured with different forms of Aspergillus fumigatus. J Med Microbiol. 2009; 58: 49–58.
Mircescu MM, Lipuma L, Van Rooijen N, Pamer EG, Hohl TM. Essential role for neutrophils but not alveolar macrophages at early time points following Aspergillus fumigatus infection. J Infect Dis. 2009; 200(4): 647–656.
Gersuk GM, Underhill DM, Zhu L, Marr KA. Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states. J Immunol. 2006; 176: 3717–3724.
Steele C, Rapaka RR, Metz A, Pop SM, Williams DL, Gordon S, Kolls JK, Brown GD. The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog. 2005; 1: e42.
Segal BH. Role of macrophages in host defense against aspergillosis and strategies for immune augmentation. Oncologist. 2007; 12(Supl. 2): 7–13.
Porter PC, Roberts L, Fields A, Knight M, Qian Y, Delclos GL, Han S, Kheradmand F, Corry DB. Necessary and sufficient role for T helper cells to prevent fungal dissemination in allergic lung disease. Infect Immun. 2011; 79(11): 4459–4471.
Bozza S, Clavaud C, Giovannini G, Fontaine T, Beauvais A, Sarfati J, D’Angelo C, Perruccio K, Bonifazi P, Zagarella S, Moretti S, Bistoni F, Latgé JP, Romani L. Immune sensing of Aspergillus fumigatus proteins, glycolipids, and polysaccharides and the impact on Th immunity and vaccination. J Immunol. 2009; 183(4): 2407–2414.
Latge JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999; 12: 310–350.
Hohl TM, Rivera A, Lipuma L, Gallegos A, Shi C, Mack M, Pamer EG. Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe. 2009; 6: 470–481.
Rivera A, Ro G, Van Epps HL, Simpson T, Leiner I, Sant’Angelo DB, Pamer EG. Innate immune activation and CD4 T cell priming during respiratory fungal infection. Immunity. 2006; 25: 665–675.
Brieland JK, Jackson C, Menzel F, Loebenberg D, Cacciapuoti A, Halpern J, Hurst S, Muchamuel T, Debets R, Kastelein R, Churakova T, Abrams J, Hare R, O’Garra A. Cytokine networking in lungs of immunocompetent mice in response to inhaled Aspergillus fumigatus. Infect Immun. 2001; 69(3): 1554–1560.
Blease K, Mehrad B, Standiford TJ, Lukacs NW, Gosling J, Boring L, Charo IF, Kunkel SL, Hogaboam CM. Enhanced pulmonary allergic responses to Aspergillus in CCR2_/_ mice. J Immunol. 2000; 165: 2603–2611.
Kurup VP, Mauze S, Choi H, Seymour BW, Coffman RL. A murine model of allergic bronchopulmonary aspergillosis with elevated eosinophils and IgE. J Immunol. 1992; 148: 3783–3788.
Lemieszek M, Chilosi M, Golec M, Skórska C, Huaux F, Yakoub Y, Pastena C, Daniele I, Cholewa G, Sitkowska J, Lisowska W, Zwoliński J, Milanowski J, Mackiewicz B, Góra A, Dutkiewicz J. Mouse model of hypersensitivity pneumonitis after inhalation exposure to different microbial antigens associated with organic dust. Ann Agric Environ Med. 2011; 18: 159–168.
Goetzl EJ, Huang MC, Kon J, Patel K, Schwartz JB, Fast K, Ferrucci L, Madara K, Taub DD, Longo DL. Gender specificity of altered human immune cytokine profiles in aging. FASEB J. 2010; 24: 3580–3589.
Martínez-Taboada V, Bartolomé MJ, Amado JA, Blanco R, García- Unzueta MT, Rodríguez-Valverde V, López-Hoyos M. Changes in peripheral blood lymphocyte subsets in elderly subjects are associated with an impaired function of the hypothalamic-pituitary-adrenal axis. Mech Ageing Dev. 2002; 123: 1477–1486.
Caruso C, Candore G, Cigna D, DiLorenzo G, Sireci G, Dieli F, Salerno A. Cytokine production pathway in the elderly. Immunol Res. 1996; 15: 84–90.
Rea I, Stewart M, Campbell P, Alexander HD, Crockard AD, Morris TC. Changes in lymphocyte subsets, interleukin, and soluble interleukin 2 receptor in old and very old age. Gerontology. 1996; 42: 69–78.
Alberti S, Cevenini E, Ostan R, Capri M, Salvioli S, Bucci L, Ginaldi L, De Martinis M, Franceschi C, Monti D. Agedependent modifications of type 1 and type 2 cytokines within virgin and memory CD4+ T cells in humans. Mech Ageing Dev. 2006; 127: 560–566.
Forsey RJ, Thompson JM, Ernerudh J, Hurst TL, Strindhall J, Johansson B, Nilsson BO, Wikby A. Plasma cytokine profiles in elderly humans. Mech Ageing Dev. 2003; 124: 487–493.
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007; 128: 92–105.
Plackett TP, Boehmer ED, Faunce DE, Kovacs EJ. Aging and innate immune system. J Leukoc Biol. 2004; 76: 291–299.
Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol. 1993; 23: 2375–2378.
Haynes L, Maué AC. Effects of aging on T cell function. Curr Opin Immunol. 2009; 21: 414–417.
Fietta A, Merlini C, Dos Santos C, Rovida S, Grassi C. Influence of aging on some specific and nonspecific mechanisms of the host defense system in 146 healthy subjects. Gerontology 1994; 40: 237–245.
Davila DR, Edwards CK 3rd, Arkins S, Simon J, Kelley KW. Interferongamma- induced priming for secretion of superoxide anion and tumor necrosis factor-alpha declines in macrophages from aged rats. FASEB J. 1990; 4: 2906–2911.
Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, Usui T, Kita T. Altered Th1/Th2 commitment in human CD4+ T cells with ageing. Clin Exp Immunol. 2000; 120: 267–273.
Karanfilov CI, Liu B, Fox CC, Lakshmanan RR, Whisler RL. Age-related defects in Th1 and Th2 cytokine production by human T cells can be dissociated from altered frequencies of CD45RA+ and CD45RO+ T cell subsets. Mech Ageing Dev. 1999; 109: 97–112.
Shearer GM. Th1/Th2 changes in aging. Mech Ageing Dev. 1997; 94: 1–5.
Uciechowski P, Kahmann L, Plümäkers B, Malavolta M, Mocchegiani E, Dedoussis G, Herbein G, Jajte J, Fulop T, Rink L. TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation. Exp Gerontol. 2008; 43: 493–498.
Chipeta J, Komada Y, Zhang XL, Deguchi T, Sugiyama K, Azuma E, Sakurai M. CD4+ and CD8+ cell cytokine profiles in neonates, older children, and adults: increasing T helper type 1 and T cytotoxic type 1 cell populations with age. Cell Immunol. 1998; 183: 149–156.
Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc. 2013; 14(12): 877–882.
Welsh P, Murray HM, Ford I, Trompet S, de Craen AJ, Jukema JW, Stott DJ, McInnes IB, Packard CJ, Westendorp RG, Sattar N. Interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk. Arterioscler Thromb Vasc Biol. 2011; 31(10): 2338–2344.
Trzonkowski P, Myśliwska J, Godlewska B, Szmit E, Łukaszuk K, Wieckiewicz J, Brydak L, Machała M, Landowski J, Myśliwski A. Immune consequences of the spontaneous pro-inflammatory status in depressed elderly patients. Brain Behav Immun. 2004; 18(2): 135–148.
Brüünsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am. 2003; 23(1): 15–39.
Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M. Immunosenescence and infectious diseases. Microbes Infect. 2001; 3(10): 851–857.
Yoshikawa TT. Epidemiology and unique aspects of aging and infectious diseases. Clin Infect Dis. 2000; 30(6): 931–933.
Brüünsgaard H: A high plasma concentration of TNF-α is associated with dementia in centenarians. J Gerontol. 1999, 54(7), 357–364.
Golec M, Skórska C, Lemieszek M, Dutkiewicz J. A novel inhalation challege to study animal model of allergic alveolitis. Ann Agric Environ Med. 2009; 16: 173–175.
Biondi PA, Chiesa LM, Storelli MR, Renon P. A new procedure for the specific high-performance liquid chromatographic determination of hydroxyproline. J Chromatogr Sci. 1997; 35: 509–512.
Kovacs EJ, Palmer JL, Fortin CF, Fülöp T Jr, Goldstein DR, Linton PJ. Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol. 2009; 30(7): 319–324.
Gomez CR, Nomellini V, Faunce DE, Kovacs EJ. Innate immunity and aging. Exp Gerontol. 2008; 43(8): 718–728.
Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol. 2004; 5(2): 133–139.
Roilides E, Dimitriadou A, Kadiltsoglou I, Sein T, Karpouzas J, Pizzo PA, Walsh TJ. IL-10 exerts suppressive and enhancing effects on antifungal activity of mononuclear phagocytes against Aspergillus fumigatus. J Immunol. 1997; 158: 322–329.
Micallef MJ, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Tanimoto T, Torigoe K, Fujii M, Ikeda M, Fukuda S, Kurimoto M. Interferon-g-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-g production. Eur J Immunol. 1996; 26: 1647–1651.
Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. Enhancement of oxidative response and damage caused by human neutrophils to Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun. 1993; 61: 1185–1193.
Rex JH, Bennett JE, Galin JI, Malech HL, Decarlo ES, Melnick DA. In vivo interferon-g augments in vitro ability of chronic granulomatous disease neutrophils to damage Aspergillus hyphae. J Infect Dis. 1991; 163: 849–852.
Cenci E, Mencacci A, Del Sero G, Bacci A, Montagnoli C, Fe d’Ostiani C, Mosci P, Bachmann M, Bistoni F, Kopf M, Romani L. Interleukin-4 causes susceptibility in invasive pulmonary aspergillosis through suppression of protective type 1 responses. J Infect Dis. 1999; 180: 1957–1968.
Nagai H, Guo J, Choi H, Kurup V. Interferon-g and tumor necrosis factor-a protect mice from invasive aspergillosis. J Infect Dis. 1995; 172: 1554–1560.
Dinarello CA. Biological basis for interleukin-1 in disease. Blood. 1996; 87: 2095–2147.
Cenci E, Mencacci A, Casagrande A, Mosci P, Bistoni F, Romani L. Impaired antifungal effector activity but not inflammatory cell recruitment in interleukin-6-deficient mice with invasive pulmonary aspergillosis. J Infect Dis. 2001; 184(5): 610–617.