Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia

BMC Pulmonary Medicine

Ralf Schubert³  Stefan Zielen³  Julia Pietzner³  Christoph Hölscher¹  Sibylle Wehner⁴  Sandra Voss³  Ruth Duecker³  Constanze Döring⁵  Eva Herrmann²  Su Youn Kim³  Olaf Eickmeier³ 

[1] Division of Infection Immunology, Research Center Borstel, Borstel, Germany;Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe-University, Frankfurt, Germany;Pediatric Pulmonology, Allergy and Cystic Fibrosis, Johann Wolfgang Goethe- University, Theodor-Stern-Kai 7, Frankfurt D-60590, Germany;Pediatric Hematology and Oncology, Johann Wolfgang Goethe- University, Frankfurt, Germany;Senckenberg Institute of Pathology, Johann Wolfgang Goethe- University, Frankfurt, Germany

关键词: Inflammation;    Acute lung injury;    ATM;    Ataxia telangiectasia;   

Others  :  862851
DOI  :  10.1186/1471-2466-14-93

 received in 2013-08-21, accepted in 2014-05-20,  发布年份 2014

【 摘 要 】

Background

Ataxia telangiectasia (A-T) is a rare but devastating and progressive disorder characterized by cerebellar dysfunction, lymphoreticular malignancies and recurrent sinopulmonary infections. In A-T, disease of the respiratory system causes significant morbidity and is a frequent cause of death.

Methods

We used a self-limited murine model of hydrochloric acid-induced acute lung injury (ALI) to determine the inflammatory answer due to mucosal injury in Atm (A-T mutated)- deficient mice (Atm^-/-).

Results

ATM deficiency increased peak lung inflammation as demonstrated by bronchoalveolar lavage fluid (BALF) neutrophils and lymphocytes and increased levels of BALF pro-inflammatory cytokines (e.g. IL-6, TNF). Furthermore, bronchial epithelial damage after ALI was increased in Atm^-/- mice. ATM deficiency increased airway resistance and tissue compliance before ALI was performed.

Conclusions

Together, these findings indicate that ATM plays a key role in inflammatory response after airway mucosal injury.

【 授权许可】

   
2014 Eickmeier et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NG, Lange K, Lathrop GM, Leppert M, Nakamura Y, O'Connell P, Paterson M, Salser W, Sanal O, Silver J, Sparkes S, Susi E, Weeks DE, Wei S, White R, Yoder F: Localization of an ataxia- telangiectasia gene to chromosome 11q22-23. Nature 1988, 336:577-580.
• [2]Bredemeyer AL, Sharma GG, Huang CY, Helmink BA, Walker LM, Khor KC, Nuskey B, Sullivan KE, Pandita TK, Bassing CH, Sleckman BP: ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 2006, 442:466-470.
• [3]Callen E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, Celeste A, Pellegrini M, McBride K, Wangsa D, Bredemeyer AL, Sleckman BP, Ried T, Nussenzweig M, Nussenzweig A: ATM prevents the persistence and propagation of chromosome breaks in lympho- cytes. Cell 2007, 130:63-75.
• [4]Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995, 268:1749-1753.
• [5]Crawford TO: Ataxia telangiectasia. Semin Pediatr Neurol 1998, 5:287-294.
• [6]Lavin MF, Shiloh Y: The genetic defect in ataxia-telangiectasia. Annu Rev Immunol 1997, 15:177-202.
• [7]Chun HH, Gatti RA: Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst) 2004, 3:1187-1196.
• [8]Gatti RA, Becker-Catania S, Chun HH, Sun X, Mitui M, Lai CH, Khanlou N, Babaei M, Cheng R, Clark C, Huo Y, Udar NC, Iyer RK: The pathogenesis of ataxia- telangiectasia. Learning from a Rosetta stone. Clin Rev Allergy Immunol 2001, 20:87-108.
• [9]Lavin MF: Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 2008, 9:759-769.
• [10]Reichenbach J, Schubert R, Schindler D, Muller K, Bohles H, Zielen S: Elevated oxidative stress in patients with ataxia telangiectasia. Antioxid Redox Signal 2002, 4:465-469.
• [11]Schubert R, Reichenbach J, Zielen S: Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia. Clin Exp Immunol 2002, 129:125-132.
• [12]Sanal O, Ersoy F, Yel L, Tezcan I, Metin A, Ozyurek H, Gariboglu S, Fikrig S, Berkel AI, Rijkers GT, Zegers BJ: Impaired IgG antibody production to pneumococcal polysaccharides in patients with ataxia-telangiectasia. J Clin Immunol 1999, 19:326-334.
• [13]Schubert R, Reichenbach J, Rose M, Zielen S: Immunogenicity of the seven valent pneumococcal conjugate vaccine in patients with ataxia- telangiectasia. Pediatr Infect Dis J 2004, 23:269-270.
• [14]Micol R, Ben Slama L, Suarez F, Le Mignot L, Beaute J, Mahlaoui N, d'Enghien Dubois C, Lauge A, Hall J, Couturier J, Vallée L, Delobel B, Rivier F, Nguyen K, Billette de Villemeur T, Stephan JL, Bordigoni P, Bertrand Y, Aladjidi N, Pedespan JM, Thomas C, Pellier I, Koenig M, Hermine O, Picard C, Moshous D, Neven B, Lanternier F, Blanche S, Tardieu M, Debré M, Fischer A, Stoppa-Lyonnet D, CEREDIH Network Investigators: Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J Allergy Clin Immunol 2011, 28:382-389.
• [15]Bagley J, Cortes ML, Breakefield XO, Iacomini J: Bone marrow transplantation restores immune system function and prevents lymphoma in Atm-deficient mice. Blood 2004, 104:572-578.
• [16]Lumsden JM, McCarty T, Petiniot LK, Shen R, Barlow C, Wynn TA, Morse HC 3rd, Gearhart PJ, Wynshaw-Boris A, Max EE, Hodes RJ: Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J Exp Med 2004, 200:1111-1121.
• [17]Pietzner J, Baer PC, Duecker RP, Merscher MB, Satzger-Prodinger C, Bechmann I, Wietelmann A, Del Turco D, Doering C, Kuci S, Bader P, Schirmer S, Zielen S, Schubert R: Bone marrow transplantation improves the outcome of Atm-deficient mice through the migration of ATM-competent cells. Hum Mol Genet 2013, 22:493-507.
• [18]Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A: Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 1996, 86:159-171.
• [19]Schubert R, Erker L, Barlow C, Yakushiji H, Larson D, Russo A, Mitchell JB, Wynshaw-Boris A: Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice. Hum Mol Genet 2004, 13:1793-1802.
• [20]Bott L, Lebreton J, Thumerelle C, Cuvellier J, Deschildre A, Sardet A: Lung disease in ataxia- telangiectasia. Acta Paediatr 2007, 96:1021-1024.
• [21]McGrath-Morrow SA, Gower WA, Rothblum-Oviatt C, Brody AS, Langston C, Fan LL, Lefton- Greif MA, Crawford TO, Troche M, Sandlund JT, Auwaerter PG, Easley B, Loughlin GM, Carroll JL, Lederman HM: Evaluation and management of pulmonary disease in ataxia-telangiectasia. Pediatr Pulmonol 2010, 45:847-859.
• [22]Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM: Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr 2004, 144:505-511.
• [23]Schroeder SA, Swift M, Sandoval C, Langston C: Interstitial lung disease in patients with ataxia-telangiectasia. Pediatr Pulmonol 2005, 39:537-543.
• [24]Schroeder SA, Zielen S: Infections of the respiratory system in patients with ataxia-telangiectasia. Pediatr Pulmonol 2014, 49:389-399.
• [25]Lefton-Greif MA, Crawford TO, Winkelstein JA, Loughlin GM, Koerner CB, Zahurak M, Lederman HM: Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia. J Pediatr 2000, 136:225-231.
• [26]Marik PE: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001, 344:665-671.
• [27]Eickmeier O, Seki H, Haworth O, Hilberath JN, Gao F, Uddin M, Croze RH, Carlo T, Pfeffer MA, Levy BD: Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol 2013, 6:256-266.
• [28]Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD: Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J Immunol 2005, 174:5033-5039.
• [29]Ehlers S, Reiling N, Hölscher C, Aly S: Measuring immune responses in vivo. Methods in Microbiology 2010, 37:227-269.
• [30]Buckley RH: Pulmonary complications of primary immunodeficiencies. Paediatr Respir Rev 2004, 5:S225-S233.
• [31]Crawford TO, Skolasky RL, Fernandez R, Rosquist KJ, Lederman HM: Survival probability in ataxia telangiectasia. Arch Dis Child 2006, 91:610-611.
• [32]Chopra C, Davies G, Taylor M, Anderson M, Bainbridge S, Tighe P, McDermott EM: Immune deficiency in Ataxia-Telangiectasia: a longitudinal study of 44 patients. Clin Exp Immunol 2014, 176:275-282.
• [33]Carlo T, Levy BD: Molecular circuits of resolution in airway inflammation. Sci World J 2010, 10:1386-1399.
• [34]Schubert R, Schmitz N, Pietzner J, Tandi C, Theisen A, Dresel R, Christmann M, Zielen S: Growth hormone supplementation increased latency to tumourigenesis in Atm-deficient mice. Growth Factors 2009, 27:265-273.
• [35]McGrath-Morrow SA, Collaco JM, Crawford TO, Carson KA, Lefton- Greif MA, Zeitlin P, Lederman HM: Elevated serum IL-8 levels in ataxia telangiectasia. J Pediatr 2010, 156(4):682-684.
• [36]McGrath-Morrow SA, Lederman HM, Aherrera AD, Lefton-Greif MA, Crawford TO, Ryan T, Wright J, Collaco JM: Pulmonary function in children and young adults with ataxia telangiectasia. Pediatr Pulmonol 2014, 49(1):84-90.
• [37]Montella S, Mollica C, Finocchi A, Pession A, Pietrogrande MC, Trizzino A, Ranucci G, Maglione M, Giardino G, Salvatore M, Santamaria F, Pignata C: Non invasive assessment of lung disease in ataxia telangiectasia by high- field magnetic resonance imaging. J Clin Immunol 2013, 33(7):1185-1191.
• [38]Westbrook AM, Schiestl RH: Atm-deficient mice exhibit increased sensitivity to dextran sulfate sodium-induced colitis characterized by elevated DNA damage and persistent immune activation. Cancer Res 2010, 70:1875-1884.
• [39]Abraham E: Neutrophils and acute lung injury. Crit Care Med 2003, 31:S195-S199.
• [40]Knight PR, Druskovich G, Tait AR, Johnson KJ: The role of neutrophils, oxidants, and proteases in the pathogenesis of acid pulmonary injury. Anesthesiology 1992, 77:772-778.
• [41]Folkesson HG, Matthay MA, Hebert CA, Broaddus VC: Acid aspiration- induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms. J Clin Invest 1995, 96:107-116.