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Identification of haptoglobin and apolipoprotein A-I as biomarkers for high altitude pulmonary edema

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Abstract

We have investigated the plasma proteome using 2D gel electrophoresis and matrix-assisted laser desorption/ionization tandem time of flight from patients with high altitude pulmonary edema (HAPE). A complete proteomic analysis was performed on 20 patients with HAPE and ten healthy sea level controls. In total, we have identified 25 protein spots in human plasma and found that 14 of them showed altered changes in HAPE patients, which mainly were acute phase proteins (APPs), compliment components, and apolipoproteins among others. Among the APPs, haptoglobin α2 chain, haptoglobin β chain, transthyretin, and plasma retinol binding precursor showed overexpression in HAPE patients as compared to controls. To validate the result of proteomic analysis, two proteins were selected for enzyme-linked immunosorbent assay and Western blotting analysis. Our data conclusively shows that two proteins, haptoglobin and apolipoprotein A-I are upregulated in plasma of HAPE patients. These proteins may provide a fast and effective control of inflammatory damage until the subsequent mechanisms can begin to operate. Taken together, our findings further support the hypothesis that inflammatory response system is linked to the pathophysiology of HAPE.

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References

  • Anderson NL, Anderson NG (2002) The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics 1:845–867

    Article  PubMed  CAS  Google Scholar 

  • Bartsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O (1991) Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 325:1284–1289

    Article  PubMed  CAS  Google Scholar 

  • Bates SR, Tao JQ, Collins HL, Francone OL, Rothblat GH (2005) Pulmonary abnormalities due to ABCA1 deficiency in mice. Am J Physiol Lung Cell Mol Physiol 289:L980–L989

    Article  PubMed  CAS  Google Scholar 

  • Belcher JD, Beckman JD, Balla G, Balla J, Vercellotti G (2009) Heme degradation and vascular injury. Antioxidant Redox Signal 12:233–248

    Article  Google Scholar 

  • Calabresi L, Franceschini G (1997) High density lipoprotein and coronary heart disease: insights from mutations leading to low high density lipoprotein. Curr Opin Lipidol 8:219–224

    Article  PubMed  CAS  Google Scholar 

  • Cecilliani F, Giordano A, Spagnolo V (2002) The systemic reaction during inflammation: the acute phase proteins. Protein Pept Lett 9:211–223

    Article  Google Scholar 

  • Cid MC, Grant DS, Hoffman GS, Auerbach R, Fauci AS, Kleinman HK (1993) Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculatis. J Clin Invest 91:977–985

    Article  PubMed  CAS  Google Scholar 

  • Cockerill GW, Gamble JR, Vadas MA (1995a) Angiogenesis: model and modulators. Int Rev Cytol 159:113–160

    Article  PubMed  CAS  Google Scholar 

  • Cockerill GW, Rye KA, Gamble JR, Vadas MA, Barter PI (1995b) High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol 15:1987–1994

    Article  PubMed  CAS  Google Scholar 

  • Doherty NS, Littman BH, Reilly K, Swindell AC, Buss JM (1998) Analysis of changes in acute-phase plasma proteins in acute inflammatory response and in rheumatoid arthritis using two-dimensional gel electrophoresis. Electrophoresis 19:355–363

    Article  PubMed  CAS  Google Scholar 

  • Durmowicz AG, Noordeweir E, Nicholas R, Reeves JT (1997) Inflammatory processes may predispose children to high-altitude pulmonary edema. J Pediatrics 130:830–840

    Article  Google Scholar 

  • Fagoonee S, Di Cunto F, Vozzi D, Volinia S, Pellegrino M, Gasparini P, Silengo L, Altruda F, Tolosano E (2006) Microarray and large-scale in silico-based identification of genes functionally related to haptoglobin and/ or hemopexin. DNA Cell Biol 25:323–330

    Article  PubMed  CAS  Google Scholar 

  • Funmei Y, Andrew JG, Damon CH, Frank JW, Christi AW, Jacqueline J (2000) Pulmonary expression of the human haptoglobin gene. Am J Respir Cell Mol Biol 23:277–282

    Google Scholar 

  • Gabay C, Kushner I (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448–454

    Article  PubMed  CAS  Google Scholar 

  • Grissom CK, Zimmerman GA, Whatley RE (1997) Endothelial selectins in acute mountain sickness and high-altitude pulmonary edema. Chest 112:1572–1578

    Article  PubMed  CAS  Google Scholar 

  • Hanaoka M, Kubo K, Yamazaki Y, Miyahara T, Matsuzawa Y, Kobayashi T, Sekiguchi M, Ota M, Watanabe H (1998) Association of high-altitude pulmonary edema with major histocompatibility complex. Circulation 97:1124–1128

    PubMed  CAS  Google Scholar 

  • Houston CS (1960) Acute pulmonary edema of high altitude. N Engl J Med 263:478–480

    Article  PubMed  CAS  Google Scholar 

  • Hulmes JD, Betheab D, Ho K, Huang S-P, Ricci DL, Opiteck GJ, Hefta SA (2004) An investigation of plasma collection, stabilization, and storage procedures for proteomic analysis of clinical samples. Clin Proteomics J 1:17–31

    Article  CAS  Google Scholar 

  • Hultgren HN (1978) High-altitude pulmonary edema. In: Staub N (ed) Lung water and solute exchange. Marcel Dekker, New York, pp 437–449

    Google Scholar 

  • Kubo K, Hanaoka M, Hayano T, Yamaguchi T, Hayano M, Hayasaka M, Koizumi T, Fujimoto K, Kobayashi T, Honda T (1996) Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary edema at moderate altitude in Japan. Thorax 51:739–742

    Article  PubMed  CAS  Google Scholar 

  • Kubo K, Hanaoka M, Hayano T, Miyahara T, Hachiya T, Hayasaka M, Koizumi T, Fujimoto K, Kobayashi T, Honda T (1998) Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema. Respir Physiol 111:301–310

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Dong, Ji B, Wu MP (2008) Human ApoA-I overexpression diminishes LPS-induced systemic inflammation and multiple organ damage in mice. Eur J Pharm 590:417–422

    Article  CAS  Google Scholar 

  • Liao XL, Lou B, Ma J, Wu MP (2005) Neutrophils activation can be diminished by apolipoprotein A-I. Life Sci 77:325–335

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Liao XL, Lou B, Wu MP (2004) Role of apolipoprotein A-I in protecting against endotoxin toxicity. Acta Biochim Biophys Sin (Shanghai) 36:419–424

    Article  CAS  Google Scholar 

  • Maciel CM, Junqueira M, Paschoal ME, Kawarmura MT, Carvalho MG, Domont GB (2005) Differential proteomic serum pattern of low molecular weight proteins expressed by adenocarcinoma lung cancer patients. J Expc Ther Oncol 5:31–38

    Google Scholar 

  • Madsen M, Graversen JH, Moestrup SK (2001) Haptoglobin and CD 163: captor and receptor gating hemoglobin to macrophages lysosomes. Redox Rep 6:386–388

    Article  PubMed  CAS  Google Scholar 

  • Moshage H (1997) Cytokines and the hepatic acute phase response. J Patho 181:257–266

    Article  CAS  Google Scholar 

  • Otera H, Ishida T, Nishiuma T, Kobayashi K, Kotani Y, Yasuda T, Kundu RK, Quertermous T, Hirata K, Nishimura Y (2009) Targeted inactivation of endothelial lipase attenuates lung allergic inflammation through raising plasma HDL level and inhibiting eosinophil infiltration. Am J Physiol Lung Cell Mol Physiol 296:L594–L602

    Article  PubMed  CAS  Google Scholar 

  • Padma T, Valli W (1989) ABO blood groups, intestinal phosphatase and haptoglobin types in patient with serum hepatitis. Hum Hered 39:345–350

    Article  Google Scholar 

  • Quaye IK (2008) Haptoglobin, inflammation and disease. Trans R Soc Trop Med Hyg 102:735–742

    Article  PubMed  CAS  Google Scholar 

  • Rodrigueza WV, Williams KJ, Rothblat GH, Philips MC (1997) Remodeling and shutting: mechanisms for the synergistic effects between different acceptor particles in the mobilization of cellular cholesterol. Arterioscler Thromb Vasc Biol 17:383–393

    Article  PubMed  CAS  Google Scholar 

  • Schifferli JA, Steiger G, Paccaud JP, Sjoholm AG (1986) Differences between C4A and C4B in the handling of immune complexes: the enhancement of CR1 binding is more important than the inhibition of immunoprecipitation. Clin Exp Immunol 63:473–477

    PubMed  CAS  Google Scholar 

  • Schlossmacher P, Hasselmann M, Meyer N, Kara F, Delabranche X, Kummerlen C, Ingenbleek Y (2002) The prognostic value of nutritional and inflammatory indices in critically ill patients with acute respiratory failure. Clin Chem Lab Med 40:1339–1343

    Article  PubMed  CAS  Google Scholar 

  • Schoene RB (1985) Pulmonary edema at high altitude: review, pathophysiology, and update. Clin Chest Med 6:491–507

    PubMed  CAS  Google Scholar 

  • Schoene RB, Hackett PH, Henderson WR, Sage EH, Chou M, Roach RC, Mills WJ, Martin TR (1986) High-altitude pulmonary edema: characteristics of lung lavage fluid. JAMA 256:63–69

    Article  PubMed  CAS  Google Scholar 

  • Schoene RB, Swenson ER, Pizzo CJ, Hackett PH, Roach RC, Mills WJ Jr, Henderson WR Jr, Martin TR (1988) The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 64:2605–2613

    PubMed  CAS  Google Scholar 

  • Schoene RB, Hultgren HN, Swenson ER (2001) High-altitude pulmonary edema. In: Hornbein TF, Schoene RB (eds) High altitude: an exploration of human adaptation. Mercel Dekker, New York, pp 777–814

    Google Scholar 

  • Wang Y, Kinzie E, Berger FG, Lim SK, Baumann H (2001) Haptoglobin, an inflammation-inducible plasma protein. Redox Rep 6:379–385

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Xu H, Shi Y, Nandedkar S, Zhang H, Gao H, Feroah T, Weihrauch D, Schult ML, Jones DW, Jarzembowski J, Sorci-Thomas M, Pritchard KA (2010) Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung. J Lipid Res 51:2560–2570

    Article  PubMed  CAS  Google Scholar 

  • West JB, Tsukimoto K, Mathieu-Costello O, Prediletto R (1991) Stress failure in pulmonary capillaries. J Appl Physiol 70:1731–1742

    PubMed  CAS  Google Scholar 

  • Yan YX, Wait R, Berkelman T, Harry RA, Westbrook JA, Wheeler CH, Dunn MJ (2000) A modified silver staning protocol for visualization of proteins compatible with matrix-assisted laser desorption/ionization and electrospray ionization-mass spectrometry. Electrophoresis 21:3666–3672

    Article  PubMed  CAS  Google Scholar 

  • Yan YJ, Li Y, Lou B, Wu MP (2006) Beneficial effects of ApoA-I on LPS-induced acute lung injury and endotoxemia in mice. Life Sci 79:210–215

    Article  PubMed  CAS  Google Scholar 

  • Yuditskaya S, Tumblin A, Hoehn GT, Wang G, Drake SK, Xu X, Ying SA, Chi H, Remaley AT, Shen RF, Munson PJ, Suffredini AF, Kato GJ (2009) Proteomic identification of altered apolipoprotein patterns in pulmonaryhypertension and vasculopathy of sickle cell disease. Blood 113:1122–1128

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, Bast RC Jr, Yu Y, Li J, Sokoll LJ, Rai AJ, Rosenzweig JM, Cameron B, Wang YY, Meng XY, Berchuck A, Van Haaften-Day C, Hacker NF, de Bruijn HW, van der Zee AG, Jacobs IJ, Fung ET, Chan DW (2004) Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 64:5882–5890

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Financial support for this study is provided by a grant from TC/321/Task—145 (YA)/ DIPAS/2008, Defence Research Development Organization (DRDO), Ministry of Defence, Government of India. We gratefully acknowledge the staff of High Altitude Medical Research, Leh for helping with the sample collection.

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Correspondence to Yasmin Ahmad.

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Y. Ahmad and D. Shukla contributed equally to this work.

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Ahmad, Y., Shukla, D., Garg, I. et al. Identification of haptoglobin and apolipoprotein A-I as biomarkers for high altitude pulmonary edema. Funct Integr Genomics 11, 407–417 (2011). https://doi.org/10.1007/s10142-011-0234-3

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  • DOI: https://doi.org/10.1007/s10142-011-0234-3

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