The “injury response”: A concept linking nonspecific injury, acute rejection, and long-term transplant outcomes

Halloran, Philip F.; Homik, Joanne; Goes, Nelson; Lui, Sing-Leung; Urmson, Joan; Ramassar, Vidyanand; Cockfield, Sandra M.

doi:10.1016/s0041-1345(96)00015-2

Cited by 212 publications

(119 citation statements)

References 15 publications

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Section: Reperfusion-rewarming Injury: the Unavoidable Second Hitmentioning

confidence: 99%

“…Endothelial cell dysfunction and activation of leukocytes contribute to the inflammatory process with the coordinated release of several cytokines and chemokines (21). It is widely held that cold ischemic injury increases allograft immunogenicity, provoking acute and chronic rejections (21,34). Whether innate and adaptive immune responses play any key role in the process and whether the immune system within the allograft contributes to the injury process are prevailing questions of considerable interest (35).…”

Section: Reperfusion-rewarming Injury: the Unavoidable Second Hitmentioning

confidence: 99%

“…Prolonged cold ischemia of deceased donor kidneys leads to higher graft dysfunction, higher recipient mortality, and higher health care costs. Furthermore, based on the "response-to-injury" hypothesis (21,34,67), injury from cold ischemia may set the stage for chronic injury. The number of patients waiting for transplantation is steadily increasing, and currently this number in the United States is close to 88,000, a threefold increase over the last decade.…”

mentioning

confidence: 99%

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Cold ischemic injury of transplanted kidneys: new insights from experimental studies

Salahudeen¹

2004

American Journal of Physiology-Renal Physiology

143

128

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Kidney transplantation is the preferred and definitive treatment for end-stage renal disease (ESRD), and kidneys from deceased donors are a major source for it. These kidneys are routinely cold stored to prolong viability, which, however, when prolonged can cause injury, resulting in reduced graft function and survival. Recent experimental studies have identified the release of iron and free radicals, activation of calpain, and formation of F2-isoprostanes as important components of cold ischemic injury, as are the swelling of mitochondria and activation of mitochondrial apoptotic pathways. Moreover, studies have also suggested that fortifying the storage solution with deferoxamine or preconditioning the donor kidneys with hemeoxygenase-1 may prove viable clinical strategies to limit cold ischemic injury. This review will summarize these and other new experimental data that have implications for reducing cold ischemic transplant injury, a step necessary to improve deceased-donor allograft survival.

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Section: Reperfusion-rewarming Injury: the Unavoidable Second Hitmentioning

confidence: 99%

Section: Reperfusion-rewarming Injury: the Unavoidable Second Hitmentioning

confidence: 99%

mentioning

confidence: 99%

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Cold ischemic injury of transplanted kidneys: new insights from experimental studies

Salahudeen¹

2004

American Journal of Physiology-Renal Physiology

143

128

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“…Our findings suggest TIMP-1 overexpression can inhibit matrilysin to prevent re-epithelialization in lung allografts resulting in a stereotypic injury response that promotes fibroproliferation and bronchiole airway obliteration. 45 …”

mentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Chen

McGuire

Hackman

et al. 2008

The American Journal of Pathology

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Obliterative bronchiolitis (OB) is the histopathological finding in chronic lung allograft rejection. Mounting evidence suggests that epithelial damage drives the development of airway fibrosis in OB. Tissue inhibitor of metalloproteinase (TIMP)-1 expression increases in lung allografts and is associated with the onset of allograft rejection. Furthermore, in a mouse model of OB, airway obliteration is reduced in TIMP-1-deficient mice. Matrilysin (matrix metallproteinase-7) is essential for airway epithelial repair and is required for the re-epithelialization of airway wounds by facilitating cell migration; therefore, the goal of this study was to determine whether TIMP-1 inhibits re-epithelialization through matrilysin. We found that TIMP-1 and matrilysin co-localized in the epithelium of human lungs with OB and both co-localized and co-immunoprecipitated in wounded primary airway epithelial cultures. TIMP-1-deficient cultures migrated faster, and epithelial cells spread to a greater extent compared with wild-type cultures. TIMP-1 also inhibited matrilysin-mediated cell migration and spreading in vitro. In vivo, TIMP-1 deficiency enhanced airway re-epithelialization after naphthalene injury. Furthermore, TIMP-1 and matrilysin co-localized in airway epithelial cells adjacent to the wound edge. Our data demonstrate that TIMP-1 interacts with matrix metalloproteinases and regulates matrilysin activity during airway epithelial repair. Furthermore, we speculate that TIMP-1 overexpression restricts airway re-epithelialization by inhibiting matrilysin activity, contributing to a stereotypic injury response that promotes airway fibrosis via bronchiole airway epithelial damage and obliteration. Bronchiolitis obliterans syndrome (BOS) is the manifestation of chronic lung rejection and limits the 5-year survival after lung transplant to less than 50%.1 In comparison, transplantations of other solid organs, such as the heart, pancreas, liver, and kidneys, have 5-year survival rates exceeding 70%.2 Obliterative bronchiolitis (OB) is the histopathological equivalent of BOS and is characterized by small airway fibrosis that contributes to progressive respiratory failure and death.3 Although the pathogenesis of OB is poorly understood, evidence suggests that the primary immunological target in the lung allograft is the airway epithelium. 4 -7 Moreover, aberrant airway re-epithelialization is apparently sufficient for the progression of fibrosis during the allograft rejection process. -13The airway epithelium is an important barrier in the innate defenses of the lung.14 After lung transplantation, persistent allo-dependent (eg, acute rejection) and alloindependent (eg, infection, ischemia) pressures on the airway epithelium necessitate rapid re-epithelialization to prevent further damage that can contribute to inflammation and fibrosis.3 Disturbances in the epithelial barrier are quickly repaired through coordinated processes by which epithelial cells bordering the injury quickly spread over the denuded basement membrane. [15][...

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“…The morbidity and mortality of affected patients remain high (1). In addition, ischemic injury to the renal allograft contributes to delayed allograft function and perhaps also initiates rejection (2,3).…”

mentioning

confidence: 99%

Docosahexaenoic Acid Ameliorates Murine Ischemic Acute Renal Failure and Prevents Increases in mRNA Abundance for both TNF-α and Inducible Nitric Oxide Synthase

Kielar¹,

Jeyarajah²,

Zhou³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. This study demonstrates that intraperitoneal injections of DHA (all cis 4,7,10,13,16,19 docosahexaenoic acid C22: n-3) bound to bovine serum albumin ameliorate murine acute renal failure (ARF) induced by temporary occlusion of the renal artery. Three micromoles of DHA decreased serum creatinine (Scr) from 2.3 mg/dl to 1.1 mg/dl 24 h after reperfusion (n ϭ 15; P Ͻ 0.05). Scr of the treated animals were significantly lower than controls throughout a 7-d time course. Although lower doses of DHA were less effective, higher doses were not more effective. Ribonuclease (RNase) protection assays showed that ischemia increased mRNA abundance for TNF-␣ and inducible nitric oxide synthase (iNOS) at 24 h. This increase was prevented by DHA administration. Because TNF-␣ and iNOS contribute to renal ischemic injury, their inhibition may contribute to DHA's salutary effect. In addition, the data may have therapeutic implications, because the DHA improves ARF even when administered at 4 h after reperfusion.

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The “injury response”: A concept linking nonspecific injury, acute rejection, and long-term transplant outcomes

Cited by 212 publications

References 15 publications

Cold ischemic injury of transplanted kidneys: new insights from experimental studies

Cold ischemic injury of transplanted kidneys: new insights from experimental studies

Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Docosahexaenoic Acid Ameliorates Murine Ischemic Acute Renal Failure and Prevents Increases in mRNA Abundance for both TNF-α and Inducible Nitric Oxide Synthase

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