Neutrophil inhibition contributes to cardioprotection by postconditioning

Granfeldt, Asger; Jiang, Rong; Wang, N. P.; Mykytenko, James; Eldaif, Shady M.; Deneve, Jeremiah; Zhao, Zhi‐Qing; Guyton, Robert A.; Tønnesen, Else; Vinten‐Johansen, Jakob

doi:10.1111/j.1399-6576.2011.02577.x

Cited by 19 publications

(13 citation statements)

References 34 publications

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“…This observation of decreased MPO positive cell infiltration with decreased tissue injury is consistent with experiments geared towards neutrophil depletion in models of myocardial and small intestine IR. 15, 17 TLR4m mice were also found to have substantially less accumulation of NETs upon reperfusion. While NETs have been previously associated with cystic fibrosis, 19 venous thrombosis, 3 bacterial sepsis, 4 and cell death, 12 this is the first demonstration that NETs are present in reperfused skeletal muscle.…”

Section: Discussionmentioning

confidence: 92%

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Öklü¹,

Albadawi²,

Jones³

et al. 2013

Journal of Vascular Surgery

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Objective Ischemia-reperfusion (IR) injury is a significant problem in the management of patients with acute limb ischemia (ALI). Despite rapid restoration of blood flow following technically successful open and endovascular revascularization, complications secondary to IR injury continue to occur and limit clinical success. Our aim was to create a murine model of hind limb IR injury to examine the role of Toll-like receptor-4 (TLR4) and to determine whether inactive TLR4 led to a decrease in the detection of neutrophil extracellular traps (NETs), which is known to be highly thrombogenic and may mediate microvascular injury. Methods A calibrated tension tourniquet was applied to unilateral hind limb of wild type (WT) and TLR4 receptor mutant (TLR4m) mice for 1.5 hours to induce ischemia and then immediately removed to initiate reperfusion. At the end of 48 hours of reperfusion, mice were sacrificed and hind limb tissue as well as serum specimens were collected for analysis. Hematoxylin and eosin stained sections of hind limb skeletal muscle tissue were examined for fiber injury. For immunohistochemistry, mouse monoclonal anti-histone H2A/H2B/DNA complex antibody to detect NETs and rabbit polyclonal anti-myeloperoxidase (MPO) antibody were used to identify infiltrating cells containing MPO. Muscle ATP levels, nuclear NF-κB activity, IκBα, poly (ADP-ribose) polymerase (PARP) activity and iNOS expression were measured. Systemic levels of KC, MCP-1 and VEGF in the serum samples were also examined. Results IR injury in the hind limb of wild type mice demonstrated significant levels of muscle fiber injury, decreased energy substrates, increased NF-κB activation, decreased I-κBα levels, increased iNOS expression and increased PARP activity levels when compared to the TLR4 knockout mice samples. Additionally, there was marked decrease in the level of neutrophil and monocyte infiltration in the TLR4 mutant mice, which corresponded to similar levels of decreased NETs detection in the interstitial space and in microvascular thrombi. In situ nuclease treatment of wild-type tissue sections significantly diminished the level of NETs immunostaining demonstrating the specificity of our antibody to detect NETs and suggesting a potential role for nuclease treatment in IR injury. Conclusions These results suggest a pivotal role for TLR4 in mediating hind limb IR injury and suggest that NETs may contribute to muscle fiber injury.

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Section: Discussionmentioning

confidence: 92%

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Öklü¹,

Albadawi²,

Jones³

et al. 2013

Journal of Vascular Surgery

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“…Medications used post-MI that directly or indirectly affect MMP production or activity. Table 1 Cell functions in the post-MI left ventricle (LV) [20,30,33,[144][145][146][147][148][149][150][151][152]. …”

Section: Resultsmentioning

confidence: 99%

Matrix Metalloproteinases: Drug Targets for Myocardial Infarction

Yabluchanskiy¹,

Li²,

Chilton³

et al. 2013

CDT

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Myocardial infarction (MI) remains a major cause of morbidity and mortality worldwide. Rapid advances in the treatment of acute MI have significantly improved short-term outcomes in patient, due in large part to successes in preventing myocardial cell death and limiting infarct area during the time of ischemia and subsequent reperfusion. Matrix metalloproteases (MMPs) play key roles in post-MI cardiac remodeling and in the development of adverse outcomes. This review highlights the importance of MMPs in the injury and remodeling response of the left ventricle and also discusses their potential as therapeutic targets Additional pre-clinical and clinical research is needed to further investigate and understand the cardioprotective effects of MMPs inhibitors.

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“…The MDA content of the lungs increases significantly following CLP-induced sepsis (43,57,58). Numerous studies have shown that IP diminishes neutrophil accumulation, lipid peroxidation and MDA levels in the lung (19,23,59–61). In the present study, the lung MDA levels were significantly higher in the sepsis group than in the IP+sepsis and sham groups.…”

Section: Discussionmentioning

confidence: 99%

Ischemic preconditioning attenuates lipid peroxidation and apoptosis in the cecal ligation and puncture model of sepsis

Olguner

Koca

Altekin

et al. 2013

Experimental and Therapeutic Medicine

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Sepsis and septic shock are are among the major causes of mortality in intensive care units. The lung and kidney are the organs most affected by sepsis. Evidence exists that lipid peroxidation and apoptosis may be responsible for the high mortality due to sepsis. Ischemic preconditioning (IP) is a method for the protection of tissues and organs against ischemia/reperfusion injury by reducing reactive oxygen species levels, lipid peroxidation and apoptosis. In the present study, the effects of IP were investigated in cecal ligation and puncture (CLP)-induced sepsis in rats. The three groups of animals used in the present controlled study were the sham-operated group (sham, n=7), which only underwent a laparotomy; the sepsis group (sepsis, n=7), which underwent cecal ligation and perforation; and the IP + sepsis group (IP+sepsis, n=7), which underwent CLP immediately prior to the application of three cycles of IP to the hind limb. The study was terminated at 6 h after the induction of CLP. Blood, kidney and lung tissue samples were collected for the determination of serum creatinine, blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL) and lung tissue malondialdehyde (MDA) levels, as well as histological examination. The serum creatinine, plasma NGAL and lung tissue MDA levels in the sepsis group were significantly increased compared with those in the sham and the IP+sepsis groups (P<0.05). Alveolar macrophage counts, histological kidney and lung injury scores, kidney (caspase 3) and lung tissue immuonreactivity (M30) scores in the sepsis group were also significantly increased compared with those in the sham and IP+sepsis groups (P<0.05). The alveolar macrophage count in the IP+sepsis group was increased compared with that in the sham group (P<0.05). In conclusion, IP inhibits lipid peroxidation and attenuates histological injury and apoptosis in the lung and kidney during sepsis.

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Neutrophil inhibition contributes to cardioprotection by postconditioning

Abstract: These data imply PMN involvement in cardioprotection by postconditioning.

Cited by 19 publications

References 34 publications

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Matrix Metalloproteinases: Drug Targets for Myocardial Infarction

Ischemic preconditioning attenuates lipid peroxidation and apoptosis in the cecal ligation and puncture model of sepsis

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