Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2017

Open Access 01-12-2017 | Research

Voluntary running exercise protects against sepsis-induced early inflammatory and pro-coagulant responses in aged mice

Authors: Karel Tyml, Scott Swarbreck, Cynthia Pape, Dan Secor, James Koropatnick, Qingping Feng, Ruud A. W. Veldhuizen, Sean E. Gill

Published in: Critical Care | Issue 1/2017

Login to get access

Abstract

Background

Despite many animal studies and clinical trials, mortality in sepsis remains high. This may be due to the fact that most experimental studies of sepsis employ young animals, whereas the majority of septic patients are elderly (60 − 70 years). The objective of the present study was to examine the sepsis-induced inflammatory and pro-coagulant responses in aged mice. Since running exercise protects against a variety of diseases, we also examined the effect of voluntary running on septic responses in aged mice.

Methods

Male C57BL/6 mice were housed in our institute from 2–3 to 22 months (an age mimicking that of the elderly). Mice were prevented from becoming obese by food restriction (given 70–90% of ad libitum consumption amount). Between 20 and 22 months, a subgroup of mice ran voluntarily on wheels, alternating 1–3 days of running with 1–2 days of rest. At 22 months, mice were intraperitoneally injected with sterile saline (control) or 3.75 g/kg fecal slurry (septic). At 7 h post injection, we examined (1) neutrophil influx in the lung and liver by measuring myeloperoxidase and/or neutrophil elastase in the tissue homogenates by spectrophotometry, (2) interleukin 6 (IL6) and KC in the lung lavage by ELISA, (3) pulmonary surfactant function by measuring percentage of large aggregates, (4) capillary plugging (pro-coagulant response) in skeletal muscle by intravital microscopy, (5) endothelial nitric oxide synthase (eNOS) protein in skeletal muscle (eNOS-derived NO is putative inhibitor of capillary plugging) by immunoblotting, and (6) systemic blood platelet counts by hemocytometry.

Results

Sepsis caused high levels of pulmonary myeloperoxidase, elastase, IL6, KC, liver myeloperoxidase, and capillary plugging. Sepsis also caused low levels of surfactant function and platelet counts. Running exercise increased eNOS protein and attenuated the septic responses.

Conclusions

Voluntary running protects against exacerbated sepsis-induced inflammatory and pro-coagulant responses in aged mice. Protection against pro-coagulant responses may involve eNOS upregulation. The present discovery in aged mice calls for clinical investigation into potential beneficial effects of exercise on septic outcomes in the elderly.
Appendix
Available only for authorised users
Literature
1.
Martin CM, Priestap F, Fisher H, Fowler RA, Heyland DK, Keenan SP, Longo CJ, Morrison T, Bentley D, Antman N, STAR Registry Investigators. A prospective, observational registry of patients with severe sepsis: the Canadian Sepsis Treatment and Response Registry. Crit Care Med. 2009;37:81–8.CrossRefPubMed
2.
Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006;34:15–21.CrossRefPubMed
3.
Dyson A, Singer M. Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Crit Care Med. 2009;37:S30–7.CrossRefPubMed
4.
Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163:1376–83.CrossRefPubMed
5.
Levi M, van der Poll T, Büller HR. Bidirectional relation between inflammation and coagulation. Circulation. 2004;109:2698–704.CrossRefPubMed
6.
Starr ME, Ueda J, Takahashi H, Weiler H, Esmon CT, Evers BM, Saito H. Age-dependent vulnerability to endotoxemia is associated with reduction of anticoagulant factors activated protein C and thrombomodulin. Blood. 2010;115:4886–93.CrossRefPubMedPubMedCentral
7.
Starr ME, Ueda J, Yamamoto S, Evers BM, Saito H. The effects of aging on pulmonary oxidative damage, protein nitration, and extracellular superoxide dismutase down-regulation during systemic inflammation. Free Radic Biol Med. 2011;50:371–80.CrossRefPubMed
8.
Turnbull IR, Clark AT, Stromberg PE, Dixon DJ, Woolsey CA, Davis CG, Hotchkiss RS, Buchman TG, Coopersmith CM. Effects of aging on the immunopathologic response to sepsis. Crit Care Med. 2009;37:1018–23.CrossRefPubMedPubMedCentral
9.
10.
Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015;25 Suppl 3:1–72.CrossRefPubMed
11.
Chen HI, Hsieh S-Y, Yang F-L, Hsu YH, Lin C-C. Exercise training attenuates septic responses in conscious rats. Med Sci Sports Exerc. 2007;39:435–42.CrossRefPubMed
12.
de Araújo CC, Silva JD, Samary CS, Guimarães IH, Marques PS, Oliveira GP, do Carmo LGRR, Goldenberg RC, Bakker-Abreu I, Diaz BL, Rocha NN, Capelozzi VL, Pelosi P, Rocco PRM. Regular and moderate exercise before experimental sepsis reduces the risk of lung and distal organ injury. J Appl Physiol. 2012;112:1206–14.CrossRefPubMed
13.
Sossdorf M, Fischer J, Meyer S, Dahlke K, Wissuwa B, Seidel C, Schrepper A, Bockmeyer CL, Lupp A, Neugebauer S, Schmerler D, Rödel J, Claus RA, Otto GP. Physical exercise induces specific adaptations resulting in reduced organ injury and mortality during severe polymicrobial sepsis. Crit Care Med. 2013;41:e246–55.CrossRefPubMed
14.
Olivo CR, Miyaji EN, Oliveira MLS, Almeida FM, Lourenço JD, Abreu RM, Arantes PMM, Lopes FD, Martins MA. Aerobic exercise attenuates pulmonary inflammation induced by Streptococcus pneumoniae. J Appl Physiol. 2014;117:998–1007.CrossRefPubMed
15.
Brun-Buisson C, Meshaka P, Pinton P, Vallet B, EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004;30:580–8.CrossRefPubMed
16.
17.
Turturro A, Witt WW, Lewis S, Hass BS, Lipman RD, Hart RW. Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. J Gerontol A Biol Sci Med Sci. 1999;54(11):B492–501.CrossRefPubMed
18.
Vachharajani V, Russell JM, Scott KL, Conrad S, Stokes KY, Tallam L, Hall J, Granger DN. Obesity exacerbates sepsis-induced inflammation and microvascular dysfunction in mouse brain. Microcirculation. 2005;12:183–94.CrossRefPubMed
19.
Bonkowski MS, Rocha JS, Masternak MM, Regaiey Al KA, Bartke A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci. 2006;103:7901–5.CrossRefPubMedPubMedCentral
20.
Wolf NS, Li Y, Pendergrass W, Schmeider C, Turturro A. Normal mouse and rat strains as models for age-related cataract and the effect of caloric restriction on its development. Exp Eye Res. 2000;70:683–92.CrossRefPubMed
21.
Garcia-Valles R, Gomez-Cabrera M, Rodriguez-Mañas L, Garcia-Garcia FJ, Diaz A, Noguera I, Olaso-Gonzalez G, Viña J. Life-long spontaneous exercise does not prolong lifespan but improves health span in mice. Longev Healthspan. 2013;2:14–2.CrossRefPubMedPubMedCentral
22.
Betik AC, Thomas MM, Wright KJ, Riel CD, Hepple RT. Exercise training from late middle age until senescence does not attenuate the declines in skeletal muscle aerobic function. Am J Physiol Regul Integr Comp Physiol. 2009;297:R744–55.CrossRefPubMed
23.
Peake J, Gatta Della P, Cameron-Smith D. Aging and its effects on inflammation in skeletal muscle at rest and following exercise-induced muscle injury. Am J Physiol Regul Integr Comp Physiol. 2010;298:R1485–95.CrossRefPubMed
24.
Maradit Kremers H, Larson DR, Crowson CS, Kremers WK, Washington RE, Steiner CA, Jiranek WA, Berry DJ. Prevalence of total hip and knee replacement in the United States. J Bone Joint Surg Am. 2015;97:1386–97.CrossRefPubMedPubMedCentral
25.
Driban JB, Hootman JM, Sitler MR, Harris K, Cattano NM. Is Participation in certain sports associated with knee osteoarthritis? A systematic review. J Athl Train. 2015:1062–6050–50.2.08.
26.
Tyml K, Li F, Wilson JX. Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med. 2008;36:2355–62.CrossRefPubMedPubMedCentral
27.
Secor D, Li F, Ellis CG, Sharpe MD, Gross PL, Wilson JX, Tyml K. Impaired microvascular perfusion in sepsis requires activated coagulation and P-selectin-mediated platelet adhesion in capillaries. Intensive Care Med. 2010;36:1928–34.CrossRefPubMedPubMedCentral
28.
Tyml K. Critical role for oxidative stress, platelets, and coagulation in capillary blood flow impairment in sepsis. Microcirculation. 2011;18:152–62.CrossRefPubMed
29.
Tyml K, Budreau CH. A new preparation of rat extensor digitorum longus muscle for intravital investigation of the microcirculation. Int J Microcirc Clin Exp. 1991;10:335–43.PubMed
30.
Veldhuizen RA, Slutsky AS, Joseph M, McCaig L. Effects of mechanical ventilation of isolated mouse lungs on surfactant and inflammatory cytokines. Eur Respir J. 2001;17:488–94.CrossRefPubMed
31.
Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–7.CrossRefPubMed
32.
Duck-Chong CG. A rapid sensitive method for determining phospholipid phosphorus involving digestion with magnesium nitrate. Lipids. 1979;14:492.CrossRef
33.
Gill SE, Huizar I, Bench EM, Sussman SW, Wang Y, Khokha R, Parks WC. Tissue inhibitor of metalloproteinases 3 regulates resolution of inflammation following acute lung injury. Am J Pathol. 2010;176:64–73.CrossRefPubMedPubMedCentral
34.
Swarbreck SB, Secor D, Ellis CG, Sharpe MD, Wilson JX, Tyml K. Short-term effect of ascorbate on bacterial content, plasminogen activator inhibitor-1, and myeloperoxidase in septic mice. J Surg Res. 2014;191:432–40.CrossRefPubMed
35.
Chua F, Laurent GJ. Neutrophil elastase: mediator of extracellular matrix destruction and accumulation. Proc Am Thorac Soc. 2006;3:424–7.CrossRefPubMed
36.
Liu H, Zhang W, Xu Z, Caldwell RW, Caldwell RB, Brooks SE. Hyperoxia causes regression of vitreous neovascularization by downregulating VEGF/VEGFR2 pathway. Invest Ophthalmol Vis Sci. 2013;54:918–31.CrossRefPubMedPubMedCentral
37.
Zhang T, Lu X, Arnold P, Liu Y, Baliga R, Huang H, Bauer JA, Liu Y, Liu Y, Feng Q. Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF-α expression and improves cardiac function during endotoxemia. Cardiovasc Res. 2012;93:471–9.CrossRefPubMed
38.
39.
Hoover DB, Ozment TR, Wondergem R, Li C, Williams DL. Impaired heart rate regulation and depression of cardiac chronotropic and dromotropic function in polymicrobial sepsis. Shock. 2015;43:185–91.CrossRefPubMedPubMedCentral
40.
House LM, Morris RT, Barnes TM, Lantier L, Cyphert TJ, McGuinness OP, Otero YF. Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance. Cardiovasc Diabetol. 2015;14:56.CrossRefPubMedPubMedCentral
41.
Cerwinka WH, Cooper D, Krieglstein CF, Feelisch M, Granger DN. Nitric oxide modulates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules. AJP: Heart Circ Physiol. 2002;282:H1111–7.
42.
Swarbreck S, Secor D, Li F, Gross PL, Ellis CG, Sharpe MD, Wilson JX, Tyml K. Effect of ascorbate on fibrinolytic factors in septic mouse skeletal muscle. Blood Coagul Fibrinolysis. 2014;25:745–53.CrossRefPubMed
43.
44.
45.
Ljubicic V, Joseph A-M, Saleem A, Uguccioni G, Collu-Marchese M, Lai RYJ, Nguyen LMD, Hood DA. Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging. Biochim Biophys Acta. 1800;2010:223–34.
46.
He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature. 2012;481:511–5.CrossRefPubMedPubMedCentral
47.
Golbidi S, Laher I. Molecular mechanisms in exercise-induced cardioprotection. Cardiol Res Pract. 2011;2011:1–15.CrossRef
48.
Bhuiyan MS, Pattison JS, Osinska H, James J, Gulick J, McLendon PM, Hill JA, Sadoshima J, Robbins J. Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest. 2013;123:5284–97.CrossRefPubMedPubMedCentral
49.
Lee-Young RS, Ayala JE, Hunley CF, James FD, Bracy DP, Kang L, Wasserman DH. Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo. Am J Physiol Regul Integr Comp Physiol. 2010;298:R1399–408.CrossRefPubMedPubMedCentral
50.
Miyauchi T, Maeda S, Iemitsu M, Kobayashi T, Kumagai Y, Yamaguchi I, Matsuda M. Exercise causes a tissue-specific change of NO production in the kidney and lung. J Appl Physiol. 2003;94:60–8.CrossRefPubMed
51.
Lam C-F, Peterson TE, Richardson DM, Croatt AJ, d'Uscio LV, Nath KA, Katusic ZS. Increased blood flow causes coordinated upregulation of arterial eNOS and biosynthesis of tetrahydrobiopterin. AJP: Heart Circ Physiol. 2006;290:H786–93.
52.
Cocks M, Wagenmakers AJM. The effect of different training modes on skeletal muscle microvascular density and endothelial enzymes controlling NO availability. J Physiol Lond. 2016;594:2245–57.CrossRefPubMed
53.
Iemitsu M, Maeda S, Jesmin S, Otsuki T, Miyauchi T. Exercise training improves aging-induced downregulation of VEGF angiogenic signaling cascade in hearts. AJP: Heart Circ Physiol. 2006;291:H1290–8.
54.
Johnson LR, Rush JW, Turk JR, Price EM, Laughlin MH. Short-term exercise training increases ACh-induced relaxation and eNOS protein in porcine pulmonary arteries. J Appl Physiol. 2001;90:1102–10.CrossRefPubMed
55.
Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88:1379–406.CrossRefPubMed
56.
Raschke S, Eckel J. Adipo-myokines: two sides of the same coin–mediators of inflammation and mediators of exercise. Mediat Inflamm. 2013;2013:320724.CrossRef
57.
Simpson RJ, Lowder TW, Spielmann G, Bigley AB, LaVoy EC, Kunz H. Exercise and the aging immune system. Ageing Res Rev. 2012;11:404–20.CrossRefPubMed
58.
Neubauer O, Sabapathy S, Lazarus R, Jowett JBM, Desbrow B, Peake JM, Cameron-Smith D, Haseler LJ, Wagner K-H, Bulmer AC. Transcriptome analysis of neutrophils after endurance exercise reveals novel signaling mechanisms in the immune response to physiological stress. J Appl Physiol. 2013;114:1677–88.CrossRefPubMed
59.
Chu AJ. Biochemical strategies to anticoagulation: a comparative overview. Curr Vasc Pharmacol. 2004;2:199–228.CrossRefPubMed
Metadata
Title
Voluntary running exercise protects against sepsis-induced early inflammatory and pro-coagulant responses in aged mice
Authors
Karel Tyml
Scott Swarbreck
Cynthia Pape
Dan Secor
James Koropatnick
Qingping Feng
Ruud A. W. Veldhuizen
Sean E. Gill
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2017
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-017-1783-1

Other articles of this Issue 1/2017

Critical Care 1/2017 Go to the issue

Letter

No-touch methods of terminal cleaning in the intensive care unit: results from the first large randomized trial with patient-centred outcomes

Letter

Patients want to be heard–loud and clear!

Research

Outcomes of subsyndromal delirium in ICU: a systematic review and meta-analysis

Research

A systematic review and meta-analysis comparing mortality in pre-hospital tracheal intubation to emergency department intubation in trauma patients

Erratum

Erratum to: Volume and its relationship to cardiac output and venous return

Research

A randomized controlled pilot study to evaluate the effect of an enteral formulation designed to improve gastrointestinal tolerance in the critically ill patient—the SPIRIT trial