Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis

BMC Immunology

Sonia M Oliani⁴  Mauro Perretti²  Roderick J Flower²  Cintia MAG Nakata¹  André LF Sampaio³  Amílcar S Damazo¹ 

[1] Department of Basic Science in Health, Faculty of Medicine, Federal University of Mato Grosso, 78060-900, Cuiabá, MT, Brazil;William Harvey Research Institute; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK;Department of Applied Pharmacology; FarManguinhos - FIOCRUZ, 21041-250, Rio de Janeiro, RJ, Brazil;Department of Biology; Instituto de Biociências, Letras e Ciências Exatas; São Paulo State University (UNESP), 15054-000, São José do Rio Preto, SP, Brazil

关键词: transforming growth factor (TGF-β);    neutrophil;    macrophage;    lung inflammation;    fibrosis;    anti-inflammation;   

Others  :  1077977
DOI  :  10.1186/1471-2172-12-59

 received in 2011-08-09, accepted in 2011-10-19,  发布年份 2011

【 摘 要 】

Background

The balancing functions of pro/anti-inflammatory mediators of the complex innate responses have been investigated in a variety of experimental inflammatory settings. Annexin-A1 (AnxA1) is one mediator of endogenous anti-inflammation, affording regulation of leukocyte trafficking and activation in many contexts, yet its role in lung pathologies has been scarcely investigated, despite being highly expressed in lung cells. Here we have applied the bleomycin lung fibrosis model to AnxA1 null mice over a 21-day time-course, to monitor potential impact of this mediator on the control of the inflammatory and fibrotic phases.

Results

Analyses in wild-type mice revealed strict spatial and temporal regulation of the Anxa1 gene, e.g. up-regulation in epithelial cells and infiltrated granulocytes at day 7, followed by augmented protein levels in alveolar macrophages by day 21. Absence of AnxA1 caused increases in: i) the degree of inflammation at day 7; and ii) indexes of fibrosis (assessed by deposition of hydroxyproline in the lung) at day 7 and 21. These alterations in AnxA1 null mice were paralleled by augmented TGF-β1, IFN-γ and TNF-α generation compared to wild-type mice. Finally, treatment of wild type animals with an AnxA1 peptido-mimetic, given prophylactically (from day 0 to 21) or therapeutically (from day 14 onward), ameliorated both signs of inflammation and fibrosis.

Conclusion

Collectively these data reveal a pathophysiological relevance for endogenous AnxA1 in lung inflammation and, more importantly, fibrosis, and may open new insights for the pharmacological treatment of lung fibrosis.

【 授权许可】

   
2011 Damazo et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Moore BB, Hogaboam CM: Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008, 294:L152-L160.
• [2]Brody AR, Salazar KD, Lankford SM: Mesenchymal stem cells modulate lung injury. Proc Am Thorac Soc 2010, 7:130-3.
• [3]Gu L, Zhu Y-J, Yang X, Guo Z-J, Xu W-B, Tian X-L: Effect of TGF-β/Smad signaling pathway on lung myofibroblast differentiation. Acta Pharmacol Sin 2007, 28:382-391.
• [4]Border WA, Noble NA: Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994, 331:1286-1292.
• [5]Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA: Transforming growth factor-b regulation of immune responses. Annu Rev Immunol 2006, 24:99-146.
• [6]Luppi F, Cerri S, Richeldi L: Steroid and/or other immunosuppressive therapies in idiopathic interstitial pneumonias: have they still a role? Sarcoidosis Vasc Diffuse Lung Dis 2005, 22:74-84.
• [7]Moeller A, Askc K, Warburton D, Gauldie J, Kolb M: The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Inter J Biochem Cell Biol 2008, 40:362-382.
• [8]Nathan C, Ding A: Nonresolving inflammation. Cell 2010, 140:871-82.
• [9]Serhan CN, Savill J: Resolution of inflammation: the beginning programs the end. Nat Immunol 2005, 6:1191-1197.
• [10]Perretti M, Flower RJ: Annexin 1 and the biology of the neutrophils. J Leukoc Biol 2004, 75:25-29.
• [11]Yang Y, Hutchinson P, Morand EF: Inhibitory effect of annexin I on synovial inflammation in rat adjuvant arthritis. Arthritis Rheum 1999, 42:1538-1544.
• [12]Damazo AS, Yona S, D'Acquisto F, Flower RJ, Oliani SM, Perretti M: Critical protective role for annexin 1 gene expression in the endotoxemic murine microcirculation. Am J Pathol 2005, 166:1607-1617.
• [13]Damazo AS, Yona S, Flower RJ, Perretti M, Oliani SM: Spatial and temporal profiles for anti-inflammatory gene expression in leukocytes during a resolving model of peritonitis. J Immunol 2006, 176:4410-4418.
• [14]Hannon R, Croxtall JD, Getting SJ, Roviezzo F, Yona S, Paul-Clark MJ, Gavins FN, Perretti M, Morris JF, Buckingham JC, Flower RJ: Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse. FASEB J 2003, 17:253-255.
• [15]Wells D, Wells K, Hannon R, Croxtall JD, Damazo AS, Oliani SM, Getting SJ, Parente L, Paul-Clark MJ, Yona S, Gavins FNE, Martin J, Christian HC, Morris JF, Perretti M, Solito E, Buckingham JC, Flower RJ: The annexin 1-/- mouse: phenotypic studies. Annexins 2004, 2:12-35.
• [16]Ambrose MP, Hunninghake GW: Corticosteroids increase lipocortin I in BAL fluid from normal individuals and patients with lung disease. J Appl Physiol 1990, 68:1668-1671.
• [17]Ambrose MP, Bahns CL, Hunninghake GW: Lipocortin I production by human alveolar macrophages. Am J Respir Cell Mol Biol 1992, 6:17-21.
• [18]Damazo AS, Paul-Clark MJ, Straus AH, Takarashi HK, Perretti M, Oliani SM: Analysis of the annexin 1 expression in rat trachea: study of the mast cell heterogeneity. Annexins 2004, 1:12-18.
• [19]Perretti M, D'Acquisto F: Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol 2009, 9:62-70.
• [20]Babbin BA, Jesaitis AJ, Ivanov AI, Kelly D, Laukoetter M, Nava P, Parkos CA, Nusrat A: Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42. J Immunol 2007, 179:8112-21.
• [21]Walther A, Riehemann K, Gerke V: A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR. Mol Cell 2000, 5:831-40.
• [22]Maderna P, Cottell DC, Toivonen T, Dufton N, Dalli J, Perretti M, Godson C: FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis. FASEB J 2010, 24:4240-9.
• [23]Perretti M, Solito E: Annexin 1 and neutrophil apoptosis. Biochem Soc Transact 2004, 32:507-510.
• [24]Tsao FH, Meyer KC, Chen X, Rosenthal NS, Hu J: Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis. Am J Respir Cell Mol Biol 1998, 18:120-128.
• [25]Dalli J, Rosignoli G, Hayhoe RP, Edelman A, Perretti M: CFTR inhibition provokes an inflammatory response associated with an imbalance of the annexin A1 pathway. Am J Pathol 2010, 177:176-86.
• [26]Weibel ER, Gomez DM: A principle for counting tissue structures on random sections. J Appl Physiol 1962, 17:343-348.
• [27]Reddy GK, Enwemeka CS: A simplified method for the analysis of hydroxyproline in biological tissues. Clin Biochem 1996, 29:225-229.
• [28]Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970, 227:680-685.
• [29]Atamas SP, White B: Cytokine regulation of pulmonary fibrosis in scleroderma. Cytokine Growth Factor Rev 2003, 14:537-550.
• [30]Karp CL, Flick LM, Yang R, Uddin J, Petasis NA: Cystic fibrosis and lipoxins. Prostaglandins Leukot Essent Fatty Acids 2005, 73:263-270.
• [31]Perretti M, Croxtall JD, Wheller SK, Goulding NJ, Hannon R, Flower RJ: Mobilizing lipocortin 1 in adherent human leukocytes downregulates their transmigration. Nat Med 1996, 2:1259-1262.
• [32]Solito E, Christian HC, Festa M, Mulla A, Tierney T, Flower RJ, Buckingham JC: Post-translational modification plays an essential role in the translocation of annexin A1 from the cytoplasm to the cell surface. FASEB J 2006, 20:1498-500.
• [33]Vong L, D'Acquisto F, Pederzoli-Ribeil M, Lavagno L, Flower RJ, Witko-Sarsat V, Perretti M: Annexin 1 cleavage in activated neutrophils: a pivotal role for proteinase. J Biol Chem 2007, 282:29998-30004.
• [34]Perretti M, Christian H, Wheller SK, Aiello I, Mugridge KG, Morris JF, Flower RJ, Goulding NJ: Annexin I is stored within gelatinase granules of human neutrophil and mobilized on the cell surface upon adhesion but not phagocytosis. Cell Biol Int 2000, 24:163-174.
• [35]Dalli J, Norling LV, Renshaw D, Cooper D, Leung KY, Perretti M: Annexin 1 mediates the rapid anti-inflammatory effects of neutrophil-derived microparticles. Blood 2008, 112:2512-2519.
• [36]See RH, Petric M, Lawrence DJ, Mok CP, Rowe T, Zitzow LA, Karunakaran KP, Voss TG, Brunham RC, Gauldie J, Finlay BB, Roper RL: Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed virus and adenovirus-vectored vaccines. J Gen Virol 2008, 89:2136-2146.
• [37]Croxtall JD, Gilroy DW, Solito E, Choudhury Q, Ward BJ, Buckingham JC, Flower RJ: Attenuation of glucocorticoid functions in an Anx-A1−/− cell line. Biochem J 2003, 371:927-935.
• [38]Violette SM, King JL, Browning RB, Pepinsky RB, Wallner BP, Sartorelli AC: Role of lipocortin I in the glucocorticoid induction of the terminal differentiation of a human squamous carcinoma. J Cel Physiol 1990, 142:70-77.
• [39]Croxtall JD, Choudhury Q, Flower RJ: Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism. Br J Pharmacol 2000, 130:289-298.
• [40]Futter CE, Felder S, Schlessinger J, Ullrich A, Hopkins CR: Annexin I is phosphorylated in the multivesicular body during the processing of the epidermal growth factor receptor. J Cell Biol 1993, 120:77-83.
• [41]Ahn SH, Sawada H, Ro JY, Nicolson GL: Differential expression of annexin I in human mammary ductal epithelial cells in normal and benign and malignant breast tissues. Clin Exp Metastasis 1997, 15:151-156.
• [42]Brichory FM, Misek DE, Yim AM, Krause MC, Giordano TJ, Beer DG, Hanash SM: An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer. Proc Natl Acad Sci USA 2001, 98:9824-9829.
• [43]Damazo AS, Moradi-Bidhendi N, Oliani SM, Flower RJ: Role of annexin 1 gene expression in mouse craniofacial bone development. Birth Defects Research (Part A) 2007, 79:524-532.
• [44]Babbin BA, Laukoetter MG, Nava P, Koch S, Lee WY, Capaldo CT, Peatman E, Severson EA, Flower RJ, Perretti M, Parkos CA, Nusrat A: Annexin A1 regulates intestinal mucosal injury, inflammation, and repair. J Immunol 2008, 181:5035-5044.
• [45]Pochetuhen K, Luzina IG, Lockatell V, Choi J, Todd NW, Atamas SP: Complex regulation of pulmonary inflammation and fibrosis by CCL18. Am J Pathol 2007, 171:428-437.
• [46]Chen ES, Greenlee BM, Wills-Karp M, Moller DR: Attenuation of lung inflammation and fibrosis in interferon-γ-deficient mice after intratracheal bleomycin. Am J Resp Cell Mol Biol 2001, 24:545-555.
• [47]Lasky JA, Brody AR: Interstitial fibrosis and growth factors. Environ Health Perspect 2000, 108:751-762.
• [48]Hardie WD, Le Cras TD, Jiang K, Tichelaar JW, Azhar M, Korfhagen TR: Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2004, 286:L741-749.
• [49]Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A: IL-13 signaling through the IL13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat Med 2006, 12:99-106.
• [50]de Coupade C, Ajuebor MN, Russo-Marie F, Perretti M, Solito E: Cytokine modulation of liver annexin 1 expression during experimental endotoxemia. Am J Pathol 2001, 159:1435-1443.
• [51]D'Acquisto F, Perretti M, Flower RJ: Annexin-A1: a pivotal regulator of the innate and adaptive immune systems. Br J Pharmacol 2008, 155:152-69.
• [52]Hayhoe RP, Kamal AM, Solito E, Flower RJ, Cooper D, Perretti M: Annexin 1 and its bioactive peptide inhibit neutrophil-endothelium interactions under flow: indication of distinct receptor involvement. Blood 2006, 107:2123-2130.