Activation of the Serotonin Pathway is Associated with Poor Outcome in COPD Exacerbation: Results of a Long-Term Cohort Study

Abstract

Background/Introduction

Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine. An increase of its activity is associated with severity in patients with pneumonia. In chronic obstructive pulmonary disease (COPD) patients, an elevation of serotonin has been reported. Experimental models showed that cigarette smoke inhibits monoamine oxidase (MAO) leading to higher levels of serotonin. We investigated the prognostic ability of tryptophan, serotonin, kynurenine, IDO, and tryptophan hydroxylase (TPH) to predict short- and long-term outcomes in patients with a COPD exacerbation.

Methods

We measured tryptophan, serotonin, and kynurenine on admission plasma samples in patients with a COPD exacerbation from a previous trial by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). IDO and TPH were calculated as ratios of kynurenine over tryptophan, and serotonin over tryptophan, respectively. We studied their association with parameters measured in clinical routine at emergency department admission representing inflammation (C-reactive protein [CRP]), infection (procalcitonin [PCT]), oxygenation (SpO2), as well as patients' clinical outcome, confirmed by structured phone interviews.

Results

Mortality in the 149 included patients was 53.7% within six years of follow-up. While IDO activity showed strong positive correlations, tryptophan was negatively correlated with CRP and PCT. For 30-day adverse outcome defined as death and/or intensive care unit (ICU) admission, a multivariate regression analysis adjusted for age and comorbidities found strong associations for IDO activity (adjusted odds ratios of 31.4 (95%CI 1.1–857), p = 0.041) and TPH (adjusted odds ratios 27.0 (95%CI 2.2–327), p = 0.010). TPH also showed a significant association with mortality at 18 months, (hazard ratio 2.61 (95%CI 1.2–5.8), p = 0.020).

Conclusion

In hospitalized patients with a COPD exacerbation, higher IDO and TPH activities independently predicted adverse short-term outcomes and TPH levels were also predictive of 18-month mortality. Whether therapeutic modulation of the serotonin pathway has positive effects on outcome needs further investigation.

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Fig. 1

Abbreviations

AUC:

Area under curve

CAP:

Community-acquired pneumonia

CI:

Confidence interval

COPD:

Chronic obstructive pulmonary disease

CRP:

C-reactive protein

ED:

Emergency department

HR:

Hazard ratio

ICU:

Intensive care unit

IDO:

Indoleamine 2,3-dioxygenase

IQR:

Interquartile range

KYN:

Kynurenine

MAO:

Monoamine oxidase

OR:

Odds ratio

PCT:

Procalcitonin

SpO2 :

Oxygen saturation

SSRI:

Selective serotonin re-uptake inhibitor

TDO:

Tryptophan 2,3-dioxygenase

TPH:

Tryptophan hydroxylase

TRP:

Tryptophan

5-HT:

Serotonin (5-hydroxytryptamine)

References

  1. 1.

    Cevikkalp SA, Loker GB, Yaman M et al (2016) A simplified HPLC method for determination of tryptophan in some cereals and legumes. Food Chem 193:26–29

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Yeung AW, Terentis AC, King NJ et al (2015) Role of indoleamine 2,3-dioxygenase in health and disease. Clin Sci 129(7):601–672

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Li Y, Hadden C, Cooper A et al (2016) Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability. Sci Rep 6:22747

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Gal EM, Sherman AD (1980) L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res 5(3):223–239

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Carlin JM, Borden EC, Sondel PM et al (1987) Biologic-response-modifier-induced indoleamine 2,3-dioxygenase activity in human peripheral blood mononuclear cell cultures. J Immunol 139(7):2414–2418

    CAS  PubMed  Google Scholar 

  6. 6.

    Hayaishi O (1976) Properties and function of indoleamine 2,3-dioxygenase. J Biochem 79(4):13P–21P

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Herraiz T, Chaparro C (2005) Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent and reversible inhibitors. Biochem Biophys Res Commun 326(2):378–386

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Khalil AA, Davies B, Castagnoli N Jr (2006) Isolation and characterization of a monoamine oxidase B selective inhibitor from tobacco smoke. Bioorg Med Chem 14(10):3392–3398

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Morecroft I, Loughlin L, Nilsen M et al (2005) Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther 313(2):539–548

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Lau WK, Chan-Yeung MM, Yip BH et al (2012) The role of circulating serotonin in the development of chronic obstructive pulmonary disease. PLoS One 7(2):e31617

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Kochanek KD, Murphy SL, Xu J et al (2016) Deaths: final data for 2014. Natl Vital Stat Rep 65(4):1–122

    PubMed  Google Scholar 

  12. 12.

    Meier MA, Ottiger M, Voegeli A et al (2017) Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study. Clin Chem Lab Med 28076309. doi:10.1515/cclm-2016-0912

  13. 13.

    Lau WK, Li X, Yeung DS et al (2012) The involvement of serotonin metabolism in cigarette smoke-induced oxidative stress in rat lung in vivo. Free Radic Res 46(11):1413–1419

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Schuetz P, Christ-Crain M, Wolbers M et al (2007) Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial. BMC Health Serv Res 7:102

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Schuetz P, Christ-Crain M, Thomann R et al (2009) Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 302(10):1059–1066

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Grolimund E, Kutz A, Marlowe RJ et al (2015) Long-term Prognosis in COPD Exacerbation: role of Biomarkers. Clin Var Exacerbation Type 12(3):295–305

    Google Scholar 

  17. 17.

    Weinberger KM (2008) Metabolomics in diagnosing metabolic diseases. Ther Umsch 65(9):487–491

    Article  PubMed  Google Scholar 

  18. 18.

    Yet I, Menni C, Shin SY et al (2016) Genetic influences on metabolite levels: a comparison across metabolomic platforms. PLoS One 11(4):e0153672

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Illig T, Gieger C, Zhai G et al (2010) A genome-wide perspective of genetic variation in human metabolism. Nat Genet 42(2):137–141

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Lepage N, McDonald N, Dallaire L et al (1997) Age-specific distribution of plasma amino acid concentrations in a healthy pediatric population. Clin Chem 43(12):2397–2402

    CAS  PubMed  Google Scholar 

  21. 21.

    Byrne GI, Lehmann LK, Landry GJ (1986) Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells. Infect Immun 53(2):347–351

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Werner ER, Fuchs D, Hausen A et al (1988) Tryptophan degradation in patients infected by human immunodeficiency virus. Biol Chem Hoppe Seyler 369(5):337–340

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Widner B, Werner ER, Schennach H et al (1997) Simultaneous measurement of serum tryptophan and kynurenine by HPLC. Clin Chem 43(12):2424–2426

    CAS  PubMed  Google Scholar 

  24. 24.

    Alan M, Grolimund E, Kutz A et al (2014) Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study. J Intern Med 278(2):174–184

    Article  Google Scholar 

  25. 25.

    Guertler C, Wirz B, Christ-Crain M et al (2011) Inflammatory responses predict long-term mortality risk in community-acquired pneumonia. Eur Respir J 37(6):1439–1446

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Changsirivathanathamrong D, Wang Y, Rajbhandari D et al (2011) Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis. Crit Care Med 39(12):2678–2683

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Hoshi M, Osawa Y, Ito H et al (2014) Blockade of indoleamine 2,3-dioxygenase reduces mortality from peritonitis and sepsis in mice by regulating functions of CD11b+ peritoneal cells. Infect Immun 82(11):4487–4495

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Wang Y, Liu H, McKenzie G et al (2010) Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 16(3):279–285

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Suzuki Y, Suda T, Yokomura K et al (2011) Serum activity of indoleamine 2,3-dioxygenase predicts prognosis of community-acquired pneumonia. J Infect 63(3):215–222

    Article  PubMed  Google Scholar 

  30. 30.

    Pawlak D, Tankiewicz A, Matys T et al (2003) Peripheral distribution of kynurenine metabolites and activity of kynurenine pathway enzymes in renal failure. J Physiol Pharmacol 54(2):175–189

    CAS  PubMed  Google Scholar 

  31. 31.

    Saito K, Fujigaki S, Heyes MP et al (2000) Mechanism of increases in L-kynurenine and quinolinic acid in renal insufficiency. Am J Physiol Ren Physiol 279(3):F565–F572

    CAS  Google Scholar 

  32. 32.

    Schefold JC, Zeden JP, Fotopoulou C et al (2009) Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol Dial Transpl 24(6):1901–1908

    CAS  Article  Google Scholar 

  33. 33.

    Holmes EW (1988) Determination of serum kynurenine and hepatic tryptophan dioxygenase activity by high-performance liquid chromatography. Anal Biochem 172(2):518–525

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Nakanishi I, Moutabarrik A, Okada N et al (1994) Interleukin-8 in chronic renal failure and dialysis patients. Nephrol Dial Transpl 9(10):1435–1442

    CAS  Google Scholar 

  35. 35.

    Zinellu A, Sotgia S, Mangoni AA et al (2015) Impact of cholesterol lowering treatment on plasma kynurenine and tryptophan concentrations in chronic kidney disease: relationship with oxidative stress improvement. Nutr Metab Cardiovasc Dis 25(2):153–159

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    de Bie J, Guest J, Guillemin GJ et al (2016) Central kynurenine pathway shift with age in women. J Neurochem 136(5):995–1003

    Article  PubMed  Google Scholar 

  37. 37.

    Mangge H, Summers KL, Meinitzer A et al (2014) Obesity-related dysregulation of the tryptophan-kynurenine metabolism: role of age and parameters of the metabolic syndrome. Obesity 22(1):195–201 (Silver Spring)

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Sugiura T, Dohi Y, Yamashita S et al (2016) Serotonin in peripheral blood reflects oxidative stress and plays a crucial role in atherosclerosis: novel insights toward holistic anti-atherothrombotic strategy. Atherosclerosis 246:157–160

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Vikenes K, Farstad M, Nordrehaug JE (1999) Serotonin is associated with coronary artery disease and cardiac events. Circulation 100(5):483–489

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Golino P, Ashton JH, Buja LM et al (1989) Local platelet activation causes vasoconstriction of large epicardial canine coronary arteries in vivo. Thromboxane A2 and serotonin are possible mediators. Circulation 79(1):154–166

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Perna G, Cogo R, Bellodi L (2004) Selective serotonin re-uptake inhibitors beyond psychiatry: are they useful in the treatment of severe, chronic, obstructive pulmonary disease? Depress Anxiety 20(4):203–204

    Article  PubMed  Google Scholar 

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Acknowledgements

We are thankful for all patients, patients’ relatives, and all local general practitioners who participated in this study. In particular, we thank the emergency department, medical clinic, and central laboratory staff of the University Hospital Basel and the Cantonal Hospitals Aarau, Liestal, Lucerne, and Muensterlingen, and the ‘Buergerspital’ Solothurn for their assistance and technical support. Finally, we acknowledge our ProHOSP Study Group for their important support.

Author Contributions

PS, MC-C, and BM created concept and design, wrote the protocol, and initiated the initial ProHOSP study. MM and PS drafted the present manuscript and performed the statistical analyses. CS, AH, and LB performed laboratory measurements of p180-Kit. All authors contributed to the data acquisition, interpretation, and drafting of the analyses, critical review for important content, and final approval of the manuscript. PS had full access to all data and takes responsibility for the accuracy of the data analysis and the integrity of the work.

The ProHOSP Study Group included: U. Schild, K. Regez, R. Bossart, C. Blum, M. Wolbers, S. Neidert, I. Suter, H.C. Bucher, F. Mueller, A. Chaudry, J. Haeuptle, R. Zarbosky, R. Fiumefreddo, M. Wieland, C. Nussbaumer, A. Christ, R. Bingisser, and K. Schneider (University Hospital Basel, Basel, Switzerland); T. Bregenzer, D. Conen, A. Huber, and J. Staehelin (Kantonsspital Aarau, Aarau, Switzerland); W. Zimmerli, C. Falconnier, and C. Bruehlhardt (Kantonsspital Baselland, Liestal, Switzerland); C. Henzen and V. Briner (Kantonsspital Luzern, Luzern, Switzerland); T. Fricker, C. Hoess, M. Krause, I. Lambinon, and M. Zueger (Kantonsspital Muensterlingen, Muensterlingen, Switzerland); and R. Thomann, R. Schoenenberger, and R. Luginbuehl (Buergerspital Solothurn, Solothurn, Switzerland).

Funding

This study was supported in part by the Swiss National Science Foundation (SNSF Professorship, PP00P3_150531/1) and the Research Council of the Kantonsspital Aarau (1410.000.044). The initial trial was funded by the Swiss National Science Foundation (Grant SNF 3200BO-116177/1), Santé Suisse, the Gottfried and Julia Bangerter-Rhyner Foundation and BRAHMS Biomarkers.

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Correspondence to Philipp Schuetz.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Meier, M.A., Ottiger, M., Vögeli, A. et al. Activation of the Serotonin Pathway is Associated with Poor Outcome in COPD Exacerbation: Results of a Long-Term Cohort Study. Lung 195, 303–311 (2017). https://doi.org/10.1007/s00408-017-0004-7

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Keywords

  • COPD
  • Serotonin
  • Outcome