Acute intratracheal Pseudomonas aeruginosa infection in cystic fibrosis mice is age-independent

Respiratory Research

Burkhard Tümmler⁵  Erich Gulbins²  Ulrich Baumann⁵  Dirk Wedekind³  Tanja Kerber-Momot⁴  Florian Wölbeling¹  Antje Munder¹ 

[1] Clinical Research Group, Clinic for Pediatric Pneumology, Allergology and Neonatology, OE 6710, Hannover Medical School, Hannover, Germany;Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany;Institute of Laboratory Animal Science, OE 8600, Hannover Medical School, Hannover, Germany;Institute for Functional and Applied Anatomy, OE 4120, Hannover Medical School, Hannover, Germany;Pediatric Pulmonology, Allergology and Neonatology, OE 6710, Hannover Medical School, Hannover, Germany

关键词: age effect;    experimental lung infection;    intratracheal;    intranasal;    Cystic fibrosis mouse models;   

Others  :  796774
DOI  :  10.1186/1465-9921-12-148

 received in 2011-08-02, accepted in 2011-11-07,  发布年份 2011

【 摘 要 】

Background

Since the discovery of the human CFTR gene in 1989 various mouse models for cystic fibrosis (CF) have been generated and used as a very suitable and popular tool to approach research on this life-threatening disease. Age related changes regarding the course of disease and susceptibility towards pulmonary infections have been discussed in numerous studies.

Methods

Here, we investigated Cftr^{TgH(neoim)Hgu} and Cftr^tm1Unc-Tg(FABPCFTR)1Jaw/J CF mice and their non-CF littermates during an acute lung infection with Pseudomonas aeruginosa for age dependent effects of their lung function and immune response.

Mice younger than three or older than six months were intratracheally infected with P. aeruginosa TBCF10839. The infection was monitored by lung function of the animals using non-invasive head-out spirometry and the time course of physiological parameters over 192 hours. Quantitative bacteriology and lung histopathology of a subgroup of animals were used as endpoint parameters.

Results

Age-dependent changes in lung function and characteristic features for CF like a shallower, faster breathing pattern were observed in both CF mouse models in uninfected state. In contrast infected CF mice did not significantly differ from their non-CF littermates in susceptibility and severity of lung infection in both mouse models and age groups. The transgenic Cftr^tm1Unc-Tg(FABPCFTR)1Jaw/J and their non-CF littermates showed a milder course of infection than the Cftr^{TgH(neoim)Hgu} CF and their congenic C57Bl/6J non-CF mice suggesting that the genetic background was more important for outcome than Cftr dysfunction.

Conclusions

Previous investigations of the same mouse lines have shown a higher airway susceptibility of older CF mice to intranasally applied P. aeruginosa. The different outcome of intranasal and intratracheal instillation of bacteria implies that infected CF epithelium is impaired during the initial colonization of upper airways, but not in the subsequent response of host defense.

【 授权许可】

   
2011 Munder et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ratjen F, Döring G: Cystic fibrosis. Lancet 2003, 361:681-689.
• [2]Davis PB, Drumm M, Konstan MW: Cystic fibrosis. Am J Respir Crit Care Med 1996, 154:1229-1256.
• [3]Gibson RL, Burns JL, Ramsey BW: Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003, 168:918-951.
• [4]Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, Birrer P, Bellon G, Berger J, Weiss T, Botzenhart K, Yankaskas JR, Randell S, Boucher RC, Döring G: Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 2002, 109:317-325.
• [5]Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N: Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989, 245:1059-1065.
• [6]Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, Drumm ML, Iannuzzi MC, Collins FS, Tsui LC: Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989, 245:1066-73.
• [7]Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC: Identification of the cystic fibrosis gene: genetic analysis. Science 1989, 245:1073-1080.
• [8]Tata F, Stanier P, Wicking C, Halford S, Kruyer H, Lench NJ, Scambler PJ, Hansen C, Braman JC, Williamson R: Cloning the mouse homolog of the human cystic fibrosis transmembrane conductance regulator gene. Genomics 1991, 10:301-307.
• [9]Yorifuji T, Lemna WK, Ballard CF, Rosenbloom CL, Rozmahel R, Plavsic N, Tsui LC, Beaudet AL: Molecular cloning and sequence analysis of the murine cDNA for the cystic fibrosis transmembrane conductance regulator. Genomics 1991, 10:547-550.
• [10]Grubb BR, Boucher RC: Pathophysiology of gene-targeted mouse models for cystic fibrosis. Physiol Rev 1999, 79:193-214.
• [11]Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M, Auerbach W, Moore A, Forstner J, Durie P, Nadeau J, Bear C, Tsui LC: Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet 1996, 12:280-287.
• [12]Haston CK, McKerlie C, Newbigging S, Corey M, Rozmahel R, Tsui LC: Detection of modifier loci influencing the lung phenotype of cystic fibrosis knockout mice. Mamm Genome 2002, 13:605-13.
• [13]Kent G, Iles R, Bear CE, Huan LJ, Griesenbach U, McKerlie C, Frndova H, Ackerley C, Gosselin D, Radzioch D, O'Brodovich H, Tsui LC, Buchwald M, Tanswell AK: Lung disease in mice with cystic fibrosis. J Clin Invest 1997, 100:3060-3069.
• [14]Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, Koller BH: An animal model for cystic fibrosis made by gene targeting. Science 1992, 257:1083-1088.
• [15]Snouwaert JN, Brigman KK, Latour AM, Iraj E, Schwab U, Gilmour MI, Koller BH: A murine model of cystic fibrosis. Am J Respir Crit Care Med 1995, 151:59-64.
• [16]Dorin JR, Dickinson P, Alton EWFW, Smith SN, Geddes DM, Stevenson BJ, Kimber WL, Fleming S, Clarke AR, Hooper ML, Anderson L, Beddington RSP, Porteous DJ: Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature 1992, 359:211-215.
• [17]Dorin JR, Stevenson BJ, Fleming S, Alton EW, Dickinson P, Porteous DJ: Long-term survival of the exon 10 insertional cystic fibrosis mutant mouse is a consequence of low level residual wild-type Cftr gene expression. Mamm Genome 1994, 5:465-472.
• [18]Zhou L, Dey CR, Wert SE, DuVall MD, Frizzell RA, Whitsett JA: Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science 1994, 266:1705-1708.
• [19]Teichgräber V, Ulrich M, Endlich N, Riethmüller J, Wilker B, De Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kürthy G, Schmid KW, Weller M, Tümmler B, Lang F, Grassme H, Döring G, Gulbins E: Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med 2008, 14:382-391.
• [20]Durie PR, Kent G, Phillips MJ, Ackerley CA: Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic fibrosis transmembrane regulator knockout murine model. Am J Pathol 2004, 164:1481-1493.
• [21]Becker KA, Tümmler B, Gulbins E, Grassmé H: Accumulation of ceramide in the trachea and intestine of cystic fibrosis mice causes inflammation and cell death. Biochem Biophys Res Commun 2010, 403:368-74.
• [22]Wölbeling F, Munder A, Stanke F, Tümmler B, Baumann U: Head-out spirometry accurately monitors the course of Pseudomonas aeruginosa lung infection in mice. Respiration 2010, 80:340-346.
• [23]Munder A, Krusch S, Tschernig T, Dorsch M, Lührmann A, van Griensven M, Tümmler B, Weiss S, Hedrich HJ: Pulmonary microbial infection in mice: Comparison of different application methods and correlation of bacterial numbers and histopathology. Exp Toxicol Pathol 2002, 54:127-133.
• [24]Charizopoulou N, Jansen S, Dorsch M, Stanke F, Dorin JR, Hedrich HJ, Tümmler B: Instability of the insertional mutation CftrTgH(neoim)Hgu cystic fibrosis mouse model. BMC Genetics 2004, 5:6.
• [25]Tóth B, Wilke M, Stanke F, Dorsch M, Jansen S, Wedekind D, Charizopoulou N, Bot A, Burmester M, Leonhard-Marek S, de Jonge HR, Hedrich HJ, Breves G, Tümmler B: Very mild disease phenotype of congenic CftrTgH(neoim)Hgu cystic fibrosis mice. BMC Genetics 2008, 9:28.
• [26]Petkov PM, Cassell MA, Sargent EE, Donnelly CJ, Robinson P, Crew V, Asquith S, Haar RV, Wiles MV: Development of a SNP genotyping panel for genetic monitoring of the laboratory mouse. Genomics 2004, 83:902-11.
• [27]Hedrich HJ, Rapp KG, Zschege C: Genetic constancy, respectively subline drifting of inbred strains of rats and mice. Z Versuchstierkd 1975, 17:263-74.
• [28]The JAX® Mice Database [http://jaxmice.jax.org/strain/002364.html] webcite
• [29]Nicklas W, Baneux P, Boot R, Decelle T, Deeny AA, Fumanelli M, Illgen-Wilcke B, FELASA (Federation of European Laboratory Animal Science Associations Working Group on Health Monitoring of Rodent and Rabbit Colonies). FELASA, London UK: Recommendations for the health monitoring of rodent and rabbit colonies in breeding and experimental units. Lab Anim 2002, 36:20-42.
• [30]National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press (US), Washington (DC); 2011.
• [31]Tümmler B, Koopmann U, Grothues D, Weissbrodt H, Steinkamp D, von der Hardt H: Nosocomial acquisition of Pseudomonas aeruginosa by cystic fibrosis patients. J Clin Microbiol 1991, 29:1265-1267.
• [32]Munder A, Zelmer A, Schmiedl A, Dittmar KE, Rohde M, Dorsch M, Otto K, Hedrich HJ, Tümmler B, Weiss S, Tschernig T: Murine pulmonary infection with Listeria monocytogenes: differential susceptibility of BALB/c, C57BL/6 and DBA/2 mice. Microbes Infect 2005, 7:600-611.
• [33]Saiman L: Microbiology of early CF lung disease. Paediatr Respir Rev 2004, 5(Suppl A):367-369.
• [34]Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, Collins J, Rock MJ, Splaingard ML: Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. JAMA 2005, 293:581-588.
• [35]Cash HA, Woods DE, McCullough B, Johanson WG Jr, Bass JA: A rat model of chronic respiratory infection with Pseudomonas aeruginosa. Am Rev Respir Dis 1979, 119:453-459.
• [36]O'Reilly T: Relevance of animal models for chronic bacterial infections in humans. Am J Respir Crit Care Med 1995, 151:2101-2107.
• [37]Pedersen SS, Shand GH, Hansen BL, Hansen GN: Induction of experimental chronic Pseudomonas aeruginosa lung infection with P. aeruginosa entrapped in alginate microspheres. APMIS 1990, 98:203-211.
• [38]Guilbault C, Saeed Z, Downey GP, Radzioch D: Cystic fibrosis mouse models. Am J Respir Cell Mol Biol 2007, 36:1-7.
• [39]Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA, Kabel AC, Wohlford-Lenane CL, Davis GJ, Hanfland RA, Smith TL, Samuel M, Wax D, Murphy CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ: Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 2008, 321:1837-1841.
• [40]Lee RJ, Foskett JK: cAMP-activated Ca2+ signaling is required for CFTR-mediated serous cell fluid secretion in porcine and human airways. J Clin Invest 2010, 120:3137-3148.
• [41]Joo NS, Cho HJ, Khansaheb M, Wine JJ: Hyposecretion of fluid from tracheal submucosal glands of CFTR-deficient pigs. J Clin Invest 2010, 120:3161-3166.
• [42]Rogan MP, Reznikov LR, Pezzulo AA, Gansemer ND, Samuel M, Prather RS, Zabner J, Fredericks DC, McCray PB Jr, Welsh MJ, Stoltz DA: Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth. Proc Natl Acad Sci USA 2010, 107:20571-5.
• [43]Chen JH, Stoltz DA, Karp PH, Ernst SE, Pezzulo AA, Moninger TO, Rector MV, Reznikov LR, Launspach JL, Chaloner K, Zabner J, Welsh MJ: Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia. Cell 2010, 143:911-23.
• [44]Ostedgaard LS, Meyerholz DK, Chen JH, Pezzulo AA, Karp PH, Rokhlina T, Ernst SE, Hanfland RA, Reznikov LR, Ludwig PS, Rogan MP, Davis GJ, Dohrn CL, Wohlford-Lenane C, Taft PJ, Rector MV, Hornick E, Nassar BS, Samuel M, Zhang Y, Richter SS, Uc A, Shilyansky J, Prather RS, McCray PB Jr, Zabner J, Welsh MJ, Stoltz DA: The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs. Sci Transl Med 2011, 3:74ra24.
• [45]Sun X, Sui H, Fisher JT, Yan Z, Liu X, Cho HJ, Joo NS, Zhang Y, Zhou W, Yi Y, Kinyon JM, Lei-Butters DC, Griffin MA, Naumann P, Luo M, Ascher J, Wang K, Frana T, Wine JJ, Meyerholz DK, Engelhardt JF: Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis. J Clin Invest 2010, 120:3149-3160.
• [46]Kubesch P, Dörk T, Wulbrand U, Kälin N, Neumann T, Wulf B, Geerlings H, Weissbrodt H, von der Hardt H, Tümmler B: Genetic determinants of airways' colonisation with Pseudomonas aeruginosa in cystic fibrosis. Lancet 1993, 341:189-193.
• [47]Kumar V, Becker T, Jansen S, van Barneveld A, Boztug K, Wölfl S, Tümmler B, Stanke F: Expression levels of FAS are regulated through an evolutionary conserved element in intron 2, which modulates cystic fibrosis disease severity. Genes Immun 2008, 9:689-696.
• [48]Boucher RC: Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med 2007, 58:157-70.
• [49]Larbig M, Jansen S, Dorsch M, Bernhard W, Bellmann B, Dorin JR, Porteous DJ, Von Der Hardt H, Steinmetz I, Hedrich HJ, Tuemmler B, Tschernig T: Residual cftr expression varies with age in cftr(tm1Hgu) cystic fibrosis mice: impact on morphology and physiology. Pathobiology 2002, 70:89-97.
• [50]Choi JY, Joo NS, Krouse ME, Wu JV, Robbins RC, Ianowski JP, Hanrahan JW, Wine JJ: Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis. J Clin Invest 2007, 117:3118-3127.
• [51]Joo NS, Cho HJ, Khansaheb M, Wine JJ: Hyposecretion of fluid from tracheal submucosal glands of CFTR-deficient pigs. J Clin Invest 2010, 120:3161-3166.
• [52]Wang EEL, Prober CG, Manson B, Corey M, Levison H: Association of respiratory viral infections with pulmonary deterioration in patients with cystic fibrosis. N Engl J Med 1984, 311:1653-1658.