Subjected to adversity, tissues oftenrespond with redoubtable resource - PDF document

Subjected to adversity, tissues oftenrespond with redoubtable resourceful-ness. Such resourcefulness enables tis-sues to endure and surmount circum-stances inimical to their vitality.Salutary responses to such stresses arediverse and include processes that dis-sipate the brunt of the imposed insult,cytoprotective mechanisms that safe-guard vulnerable cellular targets, meta-bolic adaptations that are energeticallymore favorable in the stressed state,reparative processes that restore theintegrity of injured sites, regenerativecrosis or apoptosis, and, finally, remod-In other instances, the outcome inthe encounter between healthy tissuesand unhealthy environments is one ofage. Insults may overwhelm extant cel-lular defenses by their severity while, bytheir precipitancy of onset, insults maydeny cells the opportunity to summonprotective responses. Such cellularunpreparedness allows injurious bio-checked and organelles to be criticallydisabled. However, the prior recruit-protective response may permit themto withstand such insults that are oth-erwise overwhelming.turbing influences not only applies topathologic states but is also fundamen-tal to physiologic ones. Homeostaticmechanisms exercised at systemic andlocal levels ensure optimal conditionsfor organ function in health and even inthe face of a changing external environ-the internal milieu, however, as occursharvested donor organs are ex-pected tosuccessfully negotiate. Harvested organsare then maintained in the cold and insolutions that, despite improvements,remain an imperfect substitute for theirnatural environment. The resumptionof what was deprived, but this reperfu-now ushers in a unique pathway ofinjury, namely, ischemia/reperfusion(I/R) damage. This pathway may impairvascular and hemodynamic integrity,inflict acute sublethal or lethal cellinjury, and instigate an acute inflam-matory response (1). I/R injury mayinduce primary nonfunction of thegraft in the immediate posttransplantperiod, and such injury, in turn, predis-chronic allograft dysfunction. Whereasthe biochemical basis for I/R injury iscomplex, at least a component of suchinjury resides in enhanced generation ofreactive oxygen species.Substrates such as fat can fuel oxida-tive stress incurred during reperfusion,lipid in donor organs, as found notinfrequently in harvested livers, maythe susceptibility of such larded livers tooxidation and to other mechanisms ofinjury during reperfusion may be abro-gated by the prior recruitment of a cyto-protective, antioxidant response; theyfocused, presciently, on one suchresponse, heme oxygenase-1 (HO-1) (2).Using the obese Zucker rat, these inves-tion of HO-1 markedly improved hepat-ic function in an ex vivo perfusionmodel and strikingly reduced not onlyhepatic injury in syngeneic hepatictransplants but also attendant mortali-ty in the recipients of these grafts.facilitates the opening of the heme ringand its conversion to biliverdin, in thecourse of which carbon monoxideevolves and iron is released; iron, inturn, fosters the synthesis of ferritin,whereas biliverdin is subsequently con-verted to bilirubin. HO was discoveredin the course of the inquiry into thecapacity of the reticuloendothelial sys-tem to degrade aged hemoglobin; formuch of the time since its discovery,HO was studied within the confines ofheme metabolism. However, interest innized that one of its isozymes, HO-1,was readily, and often copiously, in-duced by diverse insults includingheme, oxidants, ischemia, hyperoxia,hypoxia, and cytokines (3, 4). Not onlyaccumulating number of circumstan-ces, such induction conferred protec-tion against tissue injury (3Ð8).The basis for the protective effects ofprevious studies remains very much adraws upon the well-established, prox-the basis for this cytoprotection (Fig-lular levels of a potential toxicant(heme) and the procurement of poten-tially cytoprotective species (ferritin,carbon monoxide, biliverdin/biliru- The Journal of Clinical Investigation|December 1999|Volume 104|Number 11Heme oxygenase-1: a redoubtable response that limits reperfusion injury in the transplanted adipose liverKarl A. NathNephrology Research Unit, Mayo Clinic, 200 First Street, SW, 542 Guggenheim Building, Rochester, Minnesota 55905, USA. Phone: (507) 284-1646; Fax: (507) 284-3757; E-mail: nath.karl@mayo.edu. See related article,Commentary bin). The heme prosthetic group isubiquitously disposed within cells,contained as it is in proteins that carryor store oxygen, mitochondrial andous other proteins. Disengaged fromits linkage with such proteins Ñ aswhen cells are injured Ñ heme providesa readily transmissible pro-oxidantspecies that can destabilize cellularorganelles; induced HO-1 may restraininjured cells (3, 4). Ferritin may confercytoprotection by its iron-sequesteringcapability and, possibly, other effects(4). Carbon monoxide is an antiapop-totic, anti-inflammatory, and vasodila-tory molecule (3, 4); bili-verdin andbilirubin are antioxidant, anti-inflam-matory species (3, 4, 9). Such actions,arising from induced HO-1, would bebeneficial to cells under stress. Howev-er, there are several caveats (4). Few, ifany, studies have directly demonstrat-ed that any of these products of HO-1specifically account for the cytopro-tection conferred by in-duced HO-1.Ironically, at one time or another intheir history, each of these products ofHO has been viewed as a perpetratorof, rather than a protector against, tis-sue injury. Additionally, in certaininjured states, induced HO-1 seems anuninvolved bystander rather than aprotectant against such injury. Finally,there is a sense that the beneficialeffects of HO-1 in injured tissue mayinvolve some recondite mechanismthat transcends any one of the cur-rently invoked pathways.The unique and remarkable contribu-tion of the study of Amersi et al. is thatthe relative lack of cadaveric donororgans. That suboptimal donor liversused effectively in transplantation pro-vides a clinically relevant strategy forthe augmentation of the donor pool.This strategy is applicable to otherorgans besides the liver. For example,ingly employed in transplantation; suchkidneys may exhibit varying amountsapproach similar to the one employedby Amersi et al. may enhance the per-formance of these older kidneys. Thebroader significance of the presentstudy, however, goes beyond such clini-an overarching biologic issue: lifespanand its determinants. The longevity ofremarkably, with the ca-pacity ofrespective cells to withstand andrespond to oxidant and other forms ofstress (10). This capacity is not fixed;rather, as shown by Amersi et al. (2),resistance to stress can be enhanced bydirectly delivering or pharmacological-ly activating a particular gene. In thisregard, and in the described setting,induced HO-1 is dramatically protec-tive: HO-1 prolongs the longevity of thegraft and the survival of the recipient,even in the face of adversity.1.Halliwell, B., and Gutteridge, J.M.C. 1999. radicals in biology and medicine. Oxford UniversityPress. Oxford, United Kingdom. 617Ð783.2.Amersi, F., et al. 1999. Upregulation of heme oxy-genase-1 protects genetically fat Zucker rat liversfrom ischemia/reperfusion injury. J. Clin. Invest.3.Maines, M.D. 1997. The heme oxygenase system:Annu. Rev.Pharmacol. Toxicol.4.Platt, J.L., and Nath, K.A. 1998. Heme oxygenase: pro-tective gene or Trojan horse. Nat. Med.5.Soares, M.P, et al. 1998. Expression of heme oxy-genase-1 can determine cardiac xenograft sur-Nat. Med. :1073Ð1077.6.Hancock, W.W., Buelow, R., Sayegh, M.H., andTurka, L.A. 1998. Antibody-induced transplantarteriosclerosis is prevented by graft expression ofanti-oxidant and anti-apoptotic genes. Nat. Med.7.Yet, S.-F., et al. 1999. Hypoxia induces severe rightventricular dilatation and infarction in heme oxy-J. Clin. Invest.8.Otterbein, L.E., et al. 1999. Exogenous adminis-tration of heme oxygenase-1 by gene transfer pro-vide protection against hyperoxia-induced lunginjury. J. Clin. Invest.9.Dore, S., et al. 1999. Bilirubin, formed by activa-tion of heme oxygenase-2, protects neuronsagainst oxidative stress injury. Proc. Natl. Acad. Sci.USA.10.Kapahi, P., Boulton, M.E., and Kirkwood, T.B.L.1999. Positive correlation between mammalianlifespan and cellular resistance to stress. The Journal of Clinical Investigation|December 1999|Volume 104|Number 11