Shock/Sepsis/Trauma/Critical Care| Volume 167, ISSUE 2, e245-e253, May 15, 2011

Download started.


Heme Oxygenase-1 Mediates the Protective Effects of Ischemic Preconditioning on Mitigating Lung Injury Induced by Lower Limb Ischemia-Reperfusion in Rats


      Lower limb ischemia-reperfusion (I/R) imposes oxidative stress, elicits inflammatory response, and subsequently induces acute lung injury. Ischemic preconditioning (IP), a process of transient I/R, mitigates the acute lung injury induced by I/R. We sought to elucidate whether the protective effects of IP involve heme oxygenase-1 (HO-1).


      Adult male rats were randomized to receive I/R, I/R plus IP, I/R plus IP plus the HO-1 inhibitor tin protoporphyrin (SnPP) (n = 12 in each group). Control groups were run simultaneously. I/R was induced by applying rubber band tourniquet high around each thigh for 3 h followed by reperfusion for 3 h. To achieve IP, three cycles of bilateral lower limb I/R (i.e., ischemia for 10 min followed by reperfusion for 10 min) were performed. IP was performed immediately before I/R. After sacrifice, degree of lung injury was determined.


      Histologic findings, together with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that I/R induced acute lung injury. I/R also caused significant inflammatory response (increases in chemokine, cytokine, and prostaglandin E2 concentrations), imposed significant oxidative stress (increases in nitric oxide and malondialdehyde concentrations), and up-regulated HO-1 expression in lung tissues. IP significantly enhanced HO-1 up-regulation and, in turn, mitigated oxidative stress, inflammatory response, and acute lung injury induced by I/R. In addition, the protective effects of IP were counteracted by SnPP.


      The protective effects of IP on mitigating acute lung injury induced by lower limb I/R are mediated by HO-1.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Surgical Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Yeager R.A.
        • Moneta G.L.
        • Taylor Jr., L.M.
        • et al.
        Surgical management of severe acute lower extremity ischemia.
        J Vasc Surg. 1992; 15: 385
        • Hossny A.
        Blunt popliteal artery injury with complete lower limb ischemia: Is routine use of temporary intraluminal arterial shunt justified?.
        J Vasc Surg. 2004; 40: 61
        • Campbell W.B.
        • Collin J.
        • Morris P.J.
        The mortality of abdominal aortic aneurysm.
        Ann R Coll Surg Engl. 1986; 68: 275
        • Yassin M.M.
        • Harkin D.W.
        • Barros D'Sa A.A.
        • et al.
        Lower limb ischemia-reperfusion injury triggers a systemic inflammatory response and multiple organ dysfunction.
        World J Surg. 2002; 26: 115
        • Jeney V.
        • Balla J.
        • Yachie A.
        • et al.
        Pro-oxidant and cytotoxic effects of circulating heme.
        Blood. 2002; 100: 879
        • Soccio M.
        • Toniato E.
        • Evangelista V.
        • et al.
        Oxidative stress and cardiovascular risk: The role of vascular NAD(P)H oxidase and its genetic variants.
        Eur J Clin Invest. 2005; 35: 305
        • Morse D.
        • Choi A.M.
        Heme oxygenase-1: The “emerging molecule” has arrived.
        Am J Respir Cell Mol Biol. 2002; 27: 8
        • Kirkby K.A.
        • Adin C.A.
        Products of heme oxygenase and their potential therapeutic applications.
        Am J Physiol Renal Physiol. 2006; 290: F563
        • Srisook K.
        • Cha Y.N.
        Super-induction of HO-1 in macrophages stimulated with lipopolysaccharide by prior depletion of glutathione decreases iNOS expression and NO production.
        Nitric Oxide. 2005; 12: 70
        • Yang S.
        • Shih H.J.
        • Chow Y.C.
        • et al.
        The protective role of heme oxygenase-1 induction on testicular tissues after testicular torsion and detorsion.
        J Urol. 2007; 177: 1928
        • Zhou J.
        • Zhu X.
        • Zhang G.
        • et al.
        Protective effect of hemoglobin-induced heme oxygenase-1 on injured lungs caused by limb ischemia-reperfusion in rats.
        Chin J Traumatol. 2002; 5: 86
        • Tapuria N.
        • Kumar Y.
        • Habib M.M.
        • et al.
        Remote ischemic preconditioning: A novel protective method from ischemia reperfusion injury–a review.
        J Surg Res. 2008; 150: 304
        • Lai I.R.
        • Chang K.J.
        • Chen C.F.
        • et al.
        Transient limb ischemia induces remote preconditioning in liver among rats: The protective role of heme oxygenase-1.
        Transplantation. 2006; 81: 1311
        • Olguner C.
        • Koca U.
        • Kar A.
        • et al.
        Ischemic preconditioning attenuates the lipid peroxidation and remote lung injury in the rat model of unilateral lower limb ischemia reperfusion.
        Acta Anaesthesiol Scand. 2006; 50: 150
        • Yang C.H.
        • Tsai P.S.
        • Wang T.Y.
        • et al.
        Dexmedetomidine-ketamine combination mitigates acute lung injury in hemorrhagic shock rats.
        Resuscitation. 2009; 80: 1204
        • Yan Z.
        • Stapleton P.P.
        • Freeman T.A.
        • et al.
        Enhanced expression of cyclooxygenase-2 and prostaglandin E2 in response to endotoxin after trauma is dependent on MAPK and NF-κB mechanisms.
        Cell Immunol. 2004; 232: 116
        • Tamion F.
        • Richard V.
        • Bonmarchand G.
        • et al.
        Induction of heme-oxygenase-1 prevents the systemic responses to hemorrhagic shock.
        Am J Respir Crit Care Med. 2001; 164: 1933
        • Huang Y.H.
        • Tsai P.S.
        • Kai Y.F.
        • et al.
        Lidocaine inhibition of inducible nitric oxide synthase and cationic amino Acid transporter-2 transcription in activated murine macrophages may involve voltage-sensitive Na+ channel.
        Anesth Analg. 2006; 102: 1739
        • Futaki N.
        • Takahashi S.
        • Kitagawa T.
        • et al.
        Selective inhibition of cyclooxygenase-2 by NS-398 in endotoxin shock rats in vivo.
        Inflamm Res. 1997; 46: 496
        • Chang K.Y.
        • Tsai P.S.
        • Huang T.Y.
        • et al.
        HO-1 Mediates the effects of HBO pretreatment against sepsis.
        J Surg Res. 2006; 136: 143
        • Alam J.
        • Stewart D.
        • Touchard C.
        • et al.
        Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene.
        J Biol Chem. 1999; 274: 26071
        • Leonard M.O.
        • Kieran N.E.
        • Howell K.
        • et al.
        Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury.
        FASEB J. 2006; 20: 2624
        • Tsai P.S.
        • Chen C.C.
        • Tsai P.S.
        • et al.
        Heme oxygenase 1, nuclear factor E2-related factor 2, and nuclear factor κB are involved in hemin inhibition of type 2 cationic amino acid transporter expression and L-arginine transport in stimulated macrophages.
        Anesthesiology. 2006; 105: 1201
        • Blackwell T.S.
        • Christman J.W.
        The role of nuclear factor-κB in cytokine gene regulation.
        Am J Respir Cell Mol Biol. 1997; 17: 3
        • Schreck R.
        • Albermann K.
        • Baeuerle P.A.
        Nuclear factor κB: An oxidative stress-responsive transcription factor of eukaryotic cells (a review).
        Free Radic Res Commun. 1992; 17: 221
        • Valen G.
        Signal transduction through nuclear factor κB in ischemia-reperfusion and heart failure.
        Basic Res Cardiol. 2004; 99: 1
        • Banning A.
        • Brigelius-Flohe R.
        NF-κB, Nrf2, and HO-1 interplay in redox-regulated VCAM-1 expression.
        Antioxid Redox Signal. 2005; 7: 889