An investigation of the resolution of inflammation (catabasis) in COPD

Respiratory Research

Alvar Agustí¹  Angel Carvajal⁴  Joan Clària²  Ana González-Périz²  Borja Cosio³  Rosa Faner³  Cristina Gomez⁴  Aina Noguera³ 

[1] Institut del Torax, Hospital Clinic, Villarroel 170 (Escalera 3, Planta 5), Barcelona, 08036, Spain;CIBER Enfermedades Hepaticas y Digestivas (CIBEREHD), Barcelona, Spain;Fundació Investigació Sanitaria Illes Balears (FISIB), CIBER Enfermedades Respiratorias (CIBERES), Mallorca, Spain;Hospital Universitario Son Espases, Palma de Mallorca, Spain

关键词: Smoking;    Inflammation;    Emphysema;    Chronic bronchitis;   

Others  :  796608
DOI  :  10.1186/1465-9921-13-101

 received in 2012-07-11, accepted in 2012-11-06,  发布年份 2012

【 摘 要 】

Background

Chronic Obstructive Pulmonary Disease (COPD) is characterized by an enhanced inflammatory response to smoking that persists despite quitting. The resolution of inflammation (catabasis) is a complex and highly regulated process where tissue resident macrophages play a key role since they phagocytose apoptotic cells (efferocytosis), preventing their secondary necrosis and the spill-over of their pro-inflammatory cytoplasmic content, and release pro-resolution and tissue repair molecules, such as TGFβ, VEGF and HGF. Because inflammation does not resolve in COPD, we hypothesized that catabasis may be abnormal in these patients.

Methods

To explore this hypothesis, we studied lung tissue samples obtained at surgery from 21 COPD patients, 22 smokers with normal spirometry and 13 non-smokers controls. In these samples we used: (1) immunohistochemistry to assess the expression of CD44, CD36, VEGF and TGFβ in lung macrophages; (2) real time PCR to determine HGF, PPARγ, TGFβ, VEGF and MMP-9 gene expression; and, (3) ELISA to quantify lipoxin A4, a lipid mediator of catabasis.

Results

We found that current and former smokers with COPD showed: (1) more inflammation (higher MMP-9 expression); (2) reduced macrophage surface expression of CD44, a key efferocytosis receptor; and, (3) similar levels of TGFβ, VEGF, HGF, PPARγ, and lipoxin A4 than smokers with normal spirometry, despite the presence of inflammation and disease.

Conclusions

These results identify several potential abnormalities of catabasis in patients with COPD.

【 授权许可】

   
2012 Noguera et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al.: Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, GOLD executive summary. Am J Respir Crit Care Med 2012.
• [2]Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al.: The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004, 350:2645-2653.
• [3]Cosio M, Saetta M, Agusti A: Immunological aspects of COPD. N Engl J Med 2009, 360:2445-2454.
• [4]Nathan C: Points of control in inflammation. Nature 2002, 420:846-852.
• [5]Serhan CN: Resolution phases of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol 2007, 25:101-137.
• [6]Vandivier RW, Henson PM, Douglas IS: Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 2006, 129:1673-1682.
• [7]Moore KJ, Rosen ED, Fitzgerald ML, Randow F, Andersson LP, Altshuler D, Milstone DS, Mortensen RM, Spiegelman BM, Freeman MW: The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat Med 2001, 7:41-47.
• [8]Vachon E, Martin R, Plumb J, Kwok V, Vandivier RW, Glogauer M, Kapus A, Wang X, Chow CW, Grinstein S, et al.: CD44 is a phagocytic receptor. Blood 2006, 107:4149-4158.
• [9]Villena C, Pozo F, Barbera JA, Vaquer P, Agusti A: The CIBERES pulmonary biobank consortium: an opportunity for cooperative international respiratory research. Eur Respir J 2011, 37:204-206.
• [10]American Thoracic Society Official Statement: Standardization of spirometry. 1994 update. Am J Respir Crit Care Med 1995, 152:1107-1136.
• [11]Roca J, Sanchis J, Agustí-Vidal A, Segarra J, Navajas D, Rodriguez-Roisín R, Casan P, Sans S: Spirometric reference values for a mediterranean population. Bull Eur Physiopathol Respir 1986, 22:217-224.
• [12]Ling SH, McDonough JE, Gosselink JV, Elliott WM, Hayashi S, Hogg JC, van Eeden SF: Patterns of retention of particulate matter in lung tissues of patients with COPD: potential role in disease progression. Chest 2011, 140:1540-1549.
• [13]Huang J, Zhu H, Wang X, Tang Q, Huang H, Wu K, Zhu J, Feng Z, Shi G: The patterns and expression of KDR in normal tissues of human internal organs. J Mol Histol 2011, 42:597-603.
• [14]Hodge S, Hodge G, Scicchitano R, Reynolds PN, Holmes M: Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol 2003, 81:289-296.
• [15]Hodge S, Hodge G, Brozyna S, Jersmann H, Holmes M, Reynolds PN: Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages. Eur Respir J 2006, 28:486-495.
• [16]Pons AR, Noguera A, Blanquer D, Sauleda J, Pons J, Agusti AGN: Phenotypic characterisation of alveolar macrophages and peripheral blood monocytes in COPD. Eur Respir J 2005, 25:647-652.
• [17]Taylor AE, Finney-Hayward TK, Quint JK, Thomas CM, Tudhope SJ, Wedzicha JA, Barnes PJ, Donnelly LE: Defective macrophage phagocytosis of bacteria in COPD. Eur Respir J 2010, 35:1039-1047.
• [18]De Boer WI, Van SA, Sont JK, Sharma HS, Stolk J, Hiemstra PS, Van Krieken JH: Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998, 158:1951-1957.
• [19]Kranenburg AR, De Boer WI, Alagappan VK, Sterk PJ, Sharma HS: Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease. Thorax 2005, 60:106-113.
• [20]Santos S, Peinado VI, Ramirez J, Morales-Blanhir J, Bastos R, Roca J, Rodriguez-Roisin R, Barbera JA: Enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003, 167:1250-1256.
• [21]Maderna P, Yona S, Perretti M, Godson C: Modulation of phagocytosis of apoptotic neutrophils by supernatant from dexamethasone-treated macrophages and annexin-derived peptide Ac(2–26). J Immunol 2005, 174:3727-3733.
• [22]Serhan CN, Savill J: Resolution of inflammation: the beginning programs the end. Nat Immunol 2005, 6:1191-1197.
• [23]Levy BD, Bonnans C, Silverman ES, Palmer LJ, Marigowda G, Israel E: Diminished lipoxin biosynthesis in severe asthma. Am J Respir Crit Care Med 2005, 172:824-830.
• [24]Planaguma A, Kazani S, Marigowda G, Haworth O, Mariani TJ, Israel E, Bleecker ER, Curran-Everett D, Erzurum SC, Calhoun WJ, et al.: Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Am J Respir Crit Care Med 2008, 178:574-582.
• [25]Levy BD, Kohli P, Gotlinger K, Haworth O, Hong S, Kazani S, Israel E, Haley KJ, Serhan CN: Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness. J Immunol 2007, 178:496-502.
• [26]Carlo T, Levy BD: Molecular circuits of resolution in airway inflammation. ScientificWorldJournal 2010, 10:1386-1399.
• [27]Vachier I, Bonnans C, Chavis C, Farce M, Godard P, Bousquet J, Chanez P: Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound. J Allergy Clin Immunol 2005, 115:55-60.
• [28]Fritscher LG, Post M, Rodrigues MT, Silverman F, Balter M, Chapman KR, Zamel N: Profile of eicosanoids in breath condensate in asthma and COPD. J Breath Res 2012, 6:026001.
• [29]Bozinovski S, Uddin M, Vlahos R, Thompson M, McQualter JL, Merritt AS, Wark PA, Hutchinson A, Irving LB, Levy BD, et al.: Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A 2012, 109:935-940.
• [30]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, 24:4240-4249.
• [31]Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Pure E, Henson PM, Noble PW: Resolution of lung inflammation by CD44. Science 2002, 296:155-158.
• [32]Petrache I, Natarajan V, Zhen L, Medler TR, Richter AT, Cho C, Hubbard WC, Berdyshev EV, Tuder RM: Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med 2005, 11:491-498.
• [33]Tuder RM, Petrache I, Elias JA, Voelkel NF, Henson PM: Apoptosis and emphysema: the missing link. Am J Respir Cell Mol Biol 2003, 28:551-554.
• [34]Huynh ML, Fadok VA, Henson PM: Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 2002, 109:41-50.
• [35]Pons AR, Sauleda J, Noguera A, Pons J, Barcelo B, Fuster A, Agusti AGN: Decreased macrophage release of TGF-β and TIMP-1 in chronic obstructive pulmonary disease. Eur Respir J 2005, 26:60-66.
• [36]Chetty C, Vanamala SK, Gondi CS, Dinh DH, Gujrati M, Rao JS: MMP-9 induces CD44 cleavage and CD44 mediated cell migration in glioblastoma xenograft cells. Cell Signal 2012, 24:549-559.
• [37]Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF: Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000, 106:1311-1319.
• [38]Silverman EK, Spira A, Pare PD: Genetics and genomics of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2009, 6:539-542.
• [39]Valent P, Cerny-Reiterer S, Herrmann H, Mirkina I, George TI, Sotlar K, Sperr WR, Horny HP: Phenotypic heterogeneity, novel diagnostic markers, and target expression profiles in normal and neoplastic human mast cells. Best Pract Res Clin Haematol 2010, 23:369-378.