An overview is presented of recent findings related to biology of aging of the lymph transport system. The authors discuss recently obtained data on the aging-associated alterations of lymphatic contractility in thoracic duct and mesenteric lymphatic vessels; on comparisons of function of aged mesenteric lymphatic vessels in situ versus isolated specimens and important conclusions which arose from these studies; on aging-associated changes in functional status of mast cells located close to aged mesenteric lymphatic vessels; on evidence of presence of oxidative stress in aged lymphatic vessels and changes in arrangement of muscle cells in their walls. The authors conclude that future continuation of the research efforts in this area is necessary and will be able to provide not only novel fundamental knowledge on the biology of lymphatic aging, but also will create solid foundation for the subsequent developments of lymphatic-oriented therapeutic interventions in many diseases of the elderly.
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References
1.
BulekbaevaLE. The volume rate of lymph flow in dogs in postnatal ontogeny. (In Russian)Zh Evol Biokhim Fiziol, 1988; 24:599–600.
2.
HollanderD, DadufalzaV. Influence of aging on vitamin A transport into the lymphatic circulation. Exp Gerontol, 1990; 25:61–65.
3.
ChevalierS, FerlandG, TuchweberB. Lymphatic absorption of retinol in young, mature, and old rats: Influence of dietary restriction. FASEB J, 1996; 10:1085–1090.
4.
GashevaOY, KnippaK, NepiushchikhZV, MuthuchamyM, GashevAA. Age-related alterations of active pumping mechanisms in rat thoracic duct. Microcirculation, 2007; 14:827–839.
5.
McHaleNG, RoddieIC. The effect of transmural pressure on pumping activity in isolated bovine lymphatic vessels. J Physiol, 1976; 261:255–269.
6.
OhhashiT, AzumaT. Physiological and pharmacological characteristics of isolated bovine mesenteric lymphatics. Vasc Neuroeff Mech, 1980; 20:322–323.
7.
BenoitJN, ZawiejaDC, GoodmanAH, GrangerHJ. Characterization of intact mesenteric lymphatic pump and its responsiveness to acute edemagenic stress. Am J Physiol, 1989; 257:H2059–2069.
8.
GashevAA. The pump function of the lymphangion and the effect on it of different hydrostatic conditions. [Russian]Fiziologicheskii Zhurnal SSSR Imeni I. M. Sechenova, 1989; 75:1737–1743.
9.
GashevAA. Physiologic aspects of lymphatic contractile function: Current perspectives. Ann NY Acad Sci, 2002; 979:178–187discussion 188–196.
10.
GashevAA, DavisMJ, DelpMD, ZawiejaDC. Regional variations of contractile activity in isolated rat lymphatics. Microcirculation, 2004; 11:477–492.
11.
GashevaOY, ZawiejaDC, GashevAA. Contraction-initiated NO-dependent lymphatic relaxation: A self-regulatory mechanism in rat thoracic duct. J Physiol, 2006; 575:821–832.
12.
GashevAA, DavisMJ, ZawiejaDC. Inhibition of the active lymph pump by flow in rat mesenteric lymphatics and thoracic duct. J Physiol, 2002; 540:1023–1037.
13.
GashevAA, DelpMD, ZawiejaDC. Inhibition of active lymph pump by simulated microgravity in rats. Am J Physiol Heart Circ Physiol, 2006; 290:H2295–2308.
14.
OhhashiT, MizunoR, IkomiF, KawaiY. Current topics of physiology and pharmacology in the lymphatic system. Pharmacol Ther, 2005; 105:165–188.
15.
GashevAA. Lymphatic vessels: Pressure- and flow-dependent regulatory reactions. Ann NY Acad Sci, 2008; 1131:100–109.
16.
GashevAA. Basic mechanisms controlling lymph transport in the mesenteric lymphatic net. Ann NY Acad Sci, 2010; 1207:E16–20.
17.
MarchettiC, CasascoaA, Di NucciaAet al.Endothelin and nitric oxide synthase in lymphatic endothelial cells: Immunolocalization in vivo and in vitro. Anat Rec, 1997; 248:490–497.
18.
HayesH, KossmannE, WilsonE, MeiningerC, ZawiejaD. Development and characterization of endothelial cells from rat microlymphatics. Lymphat Res Biol, 2003; 1:101–119.
19.
OhhashiT, TakahashiN. Acetylcholine-induced release of endothelium-derived relaxing factor from lymphatic endothelial cells. Am J Physiol, 1991; 260:H1172–1178.
20.
YokoyamaS, OhhashiT. Effects of acetylcholine on spontaneous contractions in isolated bovine mesenteric lymphatics. Am J Physiol, 1993; 264:H1460–1464.
21.
ShirasawaY, IkomiF, OhhashiT. Physiological roles of endogenous nitric oxide in lymphatic pump activity of rat mesentery in vivo. Am J Physiol, 2000; 278:G551–556.
22.
RabinovitzAJ, SaphirO. The thoracic duct; Significance of age-related changes and of lipid in the wall. Circulation, 1965; 31:899–905.
23.
OrlovRS, BorisovAV, BorisovaRP. Lymphatic vessels. Structure and mechanisms of contractile activity. (In Russian), 1983Leningrad, USSR: Nauka253 pages.
24.
NagaiT, BridenbaughEA, GashevAA. Aging-associated alterations in contractility of rat mesenteric lymphatic vessels. Microcirculation, 2011; 18:463–473.
25.
MuthuchamyM, GashevA, BoswellN, DawsonN, ZawiejaD. Molecular and functional analyses of the contractile apparatus in lymphatic muscle. FASEB J, 2003; 17:920–922.
26.
DixonJB, GreinerST, GashevAA, CoteGL, MooreJE, ZawiejaDC. Lymph flow, shear stress, and lymphocyte velocity in rat mesenteric prenodal lymphatics. Microcirculation, 2006; 13:597–610.
27.
BohlenHG, WangW, GashevA, GashevaO, ZawiejaD. Phasic contractions of rat mesenteric lymphatics increase basal and phasic nitric oxide generation in vivo. Am J Physiol Heart Circ Physiol, 2009; 297:H1319–328.
28.
DavisMJ, DavisAM, KuCW, GashevAA. Myogenic constriction and dilation of isolated lymphatic vessels. Am J Physiol Heart Circ Physiol, 2009; 296:H293–302.
29.
GashevAA, ZawiejaDC. Hydrodynamic regulation of lymphatic transport and the impact of aging. Pathophysiology, 2010; 17:277–287.
30.
AklTJ, NagaiT, CoteGL, GashevAA. Mesenteric lymph flow in adult and aged rats. Am J Physiol Heart Circ Physiol, 2011; 301:H1828–1840.
31.
BenoitJN. Relationships between lymphatic pump flow and total lymph flow in the small intestine. Am J Physiol, 1991; 261:H1970–1978.
32.
OhhashiT, YokoyamaS. Nitric oxide and the lymphatic system. Jap J Physiol, 1994; 44:327–342.
33.
MizunoR, KollerA, KaleyG. Regulation of the vasomotor activity of lymph microvessels by nitric oxide and prostaglandins. Am J Physiol, 1998; 274:R790–796.
34.
von der WeidPY, ZhaoJ, Van HeldenDF. Nitric oxide decreases pacemaker activity in lymphatic vessels of guinea pig mesentery. Am J Physiol, 2001; 280:H2707–2716.
35.
ChatterjeeV, GashevAA. Aging-associated shifts in functional status of mast cells located by adult and aged mesenteric lymphatic vessels. Am J Physiol Heart Circ Physiol, 2012; 303:H693–702.
MalaviyaR, GeorgesA. Regulation of mast cell-mediated innate immunity during early response to bacterial infection. Clin Rev Allergy Immunol, 2002; 22:189–204.
45.
MarshallJS, KingCA, McCurdyCJD. Mast cell cytokine and chemokine responses to bacterial and viral infection. Curr Pharma Design, 2003; 9:11–24.
46.
MarshallJS. Mast-cell responses to pathogens. Nature Rev Immunol, 2004; 4:787–799.
47.
DawickiW, MarshallJS. New and emerging roles for mast cells in host defence. Current Opin Immunol, 2007; 19:31–38.
48.
RaibleDG, SchulmanES, DiMuzioJ, CardilloR, PostTJ. Mast cell mediators prostaglandin-D2 and histamine activate human eosinophils. J Immunol, 1992; 148:3536–3542.
49.
RamosCD, Heluy-NetoNE, RibeiroRA, FerreiraSH, CunhaFQ. Neutrophil migration induced by IL-8-activated mast cells is mediated by CINC-1. Cytokine, 2003; 21:214–223.
50.
HeibV, BeckerM, WargerTet al.Mast cells are crucial for early inflammation, migration of Langerhans cells, and CTL responses following topical application of TLR7 ligand in mice. Blood, 2007; 110:946–953.
51.
DawickiW, JawdatDW, XuN, MarshallJS. Mast cells, histamine, and IL-6 regulate the selective influx of dendritic cell subsets into an inflamed lymph node. J Immunol, 2010; 184:2116–2123.
52.
MigallyNB, TuckerA, GreenleesK, WrightM, ZambernardJ. Density and ultrastructure of mast cells in lung vessels of aging rats exposed to and recovering from chronic hypoxia. Cell Tissue Res, 1983; 232:601–608.
53.
HartPH, GrimbaldestonMA, HosszuEK, SwiftGJ, NoonanFP, Finlay-JonesJJ. Age-related changes in dermal mast cell prevalence in BALB/c mice: Functional importance and correlation with dermal mast cell expression of Kit. Immunology, 1999; 98:352–356.
54.
GuninAG, KornilovaNK, VasilievaOV, PetrovVV. Age-related changes in proliferation, the numbers of mast cells, eosinophils, and cd45-positive cells in human dermis. J Gerontol Biol Sci Med Sci, 2011; 66:385–392.
55.
BeckmanKB, AmesBN. The free radical theory of aging matures. Physiol Rev, 1998; 78:547–581.
56.
MarinJ, Rodriguez-MartinezMA. Nitric oxide, oxygen-derived free radicals and vascular endothelium. J Auton Pharmacol, 1995; 15:279–307.
57.
MayhanWG. Superoxide dismutase partially restores impaired dilatation of the basilar artery during diabetes mellitus. Brain Res, 1997; 760:204–209.
58.
DidionSP, HathawayCA, FaraciFM. Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD. Am J Physiol Heart Circ Physiol, 2001; 281:H1697–1703.
59.
DidionSP, RyanMJ, DidionLA, FeganPE, SigmundCD, FaraciFM. Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice. Circ Res, 2002; 91:938–444.
60.
DidionSP, RyanMJ, BaumbachGL, SigmundCD, FaraciFM. Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen. Am J Physiol Heart Circ Physiol, 2002; 283:H1569–1576.
61.
PacherP, BeckmanJS, LiaudetL. Nitric oxide and peroxynitrite in health and disease. Physiol Rev, 2007; 87:315–424.
62.
ChuY, AlwahdaniA, IidaS, LundDD, FaraciFM, HeistadDD. Vascular effects of the human extracellular superoxide dismutase R213G variant. Circulation, 2005; 112:1047–1053.
63.
BrownKA, ChuT, LundDD, HeistadDD, FaraciFM. Gene transfer of extracellular superoxide dismutase protects against vascular dysfunction with aging. Am J Physiol Heart Circ Physiol, 2006; 290:H2600–2605.
64.
BrownKA, DidionSP, AndresenJJ, FaraciFM. Effect of aging, MnSOD deficiency, and genetic background on endothelial function: evidence for MnSOD haploinsufficiency. ArterioscleR Thromb Vasc Biol, 2007; 27:1941–1946.
GongoraMC, QinZ, LaudeKet al.Role of extracellular superoxide dismutase in hypertension. Hypertension, 2006; 48:473–481.
79.
JungO, MarklundSL, GeigerH, PedrazziniT, BusseR, BrandesRP. Extracellular superoxide dismutase is a major determinant of nitric oxide bioavailability: In vivo and ex vivo evidence from ecSOD-deficient mice. Circ Res, 2003; 93:622–629.
SunD, HuangA, YanEHet al.Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats. Am J Physiol Heart Circ Physiol, 2004; 286:H2249–2256.
84.
CookeCL, DavidgeST. Endothelial-dependent vasodilation is reduced in mesenteric arteries from superoxide dismutase knockout mice. Cardiovasc Res, 2003; 60:635–642.
85.
VeerareddyS, CookeCL, BakerPN, DavidgeST. Gender differences in myogenic tone in superoxide dismutase knockout mouse: Animal model of oxidative stress. Am J Physiol Heart Circ Physiol, 2004; 287:H40–45.
86.
BeckmanJS, IschiropoulosH, ZhuLet al.Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite. Arch Biochem Biophys, 1992; 298:438–445.
87.
WeiYH, MaYS, LeeHC, LeeCF, LuCY. Mitochondrial theory of aging matures—Roles of mtDNA mutation and oxidative stress in human aging. Zhonghua Yi Xue Za Zhi (Taipei), 2001; 64:259–270.
88.
GoldsteinS, CzapskiG, LindJ, MerenyiG. Tyrosine nitration by simultaneous generation of (.)NO and O-(2) under physiological conditions. How the radicals do the job. J Biol Chem, 2000; 275:3031–3036.
89.
AulakKS, KoeckT, CrabbJW, StuehrDJ. Dynamics of protein nitration in cells and mitochondria. Am J Physiol Heart Circ Physiol, 2004; 286:H30–8.
