Treatment of deep sternal wound infections post‐open heart surgery by application of activated macrophage suspension

Orenstein, Arie; Kachel, Erez; Zuloff-Shani, Adi; Paz, Yosef; Sarig, Oren; Haik, Josef; Smolinsky, Aram Kurtz; Mohr, Raphael; Shinar, Eilat; Danon, D.

doi:10.1111/j.1067-1927.2005.130304.x

Cited by 27 publications

(21 citation statements)

References 47 publications

(59 reference statements)

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“…Timely recruitment of macrophages is necessary for wound healing (24,25). In the nonischemic wounds, macrophage recruitment was markedly compromised, consistent with our observation in the preclinical setting (4).…”

Section: Discussionsupporting

confidence: 85%

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Biswas¹,

Roy²,

Banerjee³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

244

199

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Ischemia complicates wound closure. Here, we are unique in presenting a murine ischemic wound model that is based on bipedicle flap approach. Using this model of ischemic wounds we have sought to elucidate how microRNAs may be implicated in limiting wound reepithelialization under hypoxia, a major component of ischemia. Ischemia, evaluated by laser Doppler as well as hyperspectral imaging, limited blood flow and lowered tissue oxygen saturation. EPR oximetry demonstrated that the ischemic wound tissue had pO 2 <10 mm Hg. Ischemic wounds suffered from compromised macrophage recruitment and delayed wound epithelialization. Specifically, epithelial proliferation, as determined by Ki67 staining, was compromised. In vivo imaging showed massive hypoxia inducible factor-1α (HIF-1α) stabilization in ischemic wounds, where HIF-1α induced miR-210 expression that, in turn, silenced its target E2F3, which was markedly down-regulated in the wound-edge tissue of ischemic wounds. E2F3 was recognized as a key facilitator of cell proliferation. In keratinocytes, knock-down of E2F3 limited cell proliferation. Forced stabilization of HIF-1α using Ad-VP16-HIF-1α under normoxic conditions upregulated miR-210 expression, down-regulated E2F3, and limited cell proliferation. Studies using cellular delivery of miR-210 antagomir and mimic demonstrated a key role of miR-210 in limiting keratinocyte proliferation. In summary, these results are unique in presenting evidence demonstrating that the hypoxia component of ischemia may limit wound re-epithelialization by stabilizing HIF-1α, which induces miR-210 expression, resulting in the down-regulation of the cell-cycle regulatory protein E2F3.skin | tissue repair | wound healing

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Section: Discussionsupporting

confidence: 85%

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Biswas¹,

Roy²,

Banerjee³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

244

199

View full text Add to dashboard Cite

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“…Third, human anti-Gal Abs immunocomplexed with α-gal epitopes readily bind to FcγR on macrophages (21, 32). Fourth, cultured human macrophages activated in vitro by hypotonic shock were found to accelerate wound healing in patients with deep sternal wounds (53) and with ulcers (7). The use of α-gal liposomes on wound dressings is likely to be much easier to perform than injection of activated macrophages into wounds because it does not require specialized equipment and facilities for in vitro culturing of macrophages.…”

Section: Discussionmentioning

confidence: 99%

Rapid Recruitment and Activation of Macrophages by Anti-Gal/α-Gal Liposome Interaction Accelerates Wound Healing

Wigglesworth

Racki

Mishra

et al. 2011

The Journal of Immunology

179

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Macrophages are pivotal in promoting wound healing. We hypothesized that topical application of liposomes with glycolipids that carry Gala1-3Galb1-4GlcNAc-R epitopes (α-gal liposomes) on wounds may accelerate the healing process by rapid recruitment and activation of macrophages in wounds. Immune complexes of the natural anti-Gal Ab (constituting ~1% of Ig in humans) bound to its ligand, the α-gal epitope on α-gal liposomes would induce local activation of complement and generation of complement chemotactic factors that rapidly recruit macrophages. Subsequent binding of the Fc portion of anti-Gal coating α-gal liposomes to FcγRs on recruited macrophages may activate macrophage genes encoding cytokines that mediate wound healing. We documented the efficacy of this treatment in α1,3galactosyltrasferase knockout mice. In contrast to wild-type mice, these knockout mice lack α-gal epitopes and can produce the anti-Gal Ab. The healing time of excisional skin wounds treated with α-gal liposomes in these mice is twice as fast as that of control wounds. Moreover, scar formation in α-gal liposome-treated wounds is much lower than in physiologic healing. Additional sonication of α-gal liposomes resulted in their conversion into submicroscopic α-gal nanoparticles. These α-gal nanoparticles diffused more efficiently in wounds and further increased the efficacy of the treatment, resulting in 95–100% regeneration of the epidermis in wounds within 6 d. The study suggests that α-gal liposome and α-gal nanoparticle treatment may enhance wound healing in the clinic because of the presence of high complement activity and high anti-Gal Ab titers in humans.

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“…Adult cutaneous tissue repair is accompanied by a robust recruitment of inflammatory cells to the wound site (46). Timely recruitment of macrophages is necessary for wound healing (34,39). In the nonischemic wounds, macrophage recruitment was rapid, peaking on day 3 and subsiding on day 7 postwounding.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a preclinical model of chronic ischemic wound

Roy

Biswas

Khanna

et al. 2009

Physiological Genomics

111

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Chronic ischemic wounds presenting at wound clinics are heterogeneous with respect to etiology, age of the wound, and other factors complicating wound healing. In addition, there are ethical challenges associated with collecting repeated biopsies from a patient to develop an understanding of the temporal dynamics of the mechanisms underlying chronic wounds. The need for a preclinical model of ischemic wound is therefore compelling. The porcine model is widely accepted as an excellent preclinical model for human wounds. A full-thickness bipedicle flap approach was adopted to cause skin ischemia. Closure of excisional wounds placed on ischemic tissue was severely impaired resulting in chronic wounds. Histologically, ischemic wounds suffered from impaired re-epithelialization, delayed macrophage recruitment and poorer endothelial cell abundance and organization. Compared with the pair-matched nonischemic wound, unique aspects of the ischemic wound biology were examined on days 3, 7, 14, and 28 by systematic screening of the wound tissue transcriptome using high-density porcine GeneChips. Ischemia markedly potentiated the expression of arginase-1, a cytosolic enzyme that metabolizes the precursor of nitric oxide l-arginine. Ischemia also induced the SOD2 in the wound tissue perhaps as survival response of the challenged tissue. Human chronic wounds also demonstrated elevated expression of SOD2 and arginase-1. This study provides a thorough database that may serve as a valuable reference tool to develop novel hypotheses aiming to elucidate the biology of ischemic chronic wounds in a preclinical setting.

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Treatment of deep sternal wound infections post‐open heart surgery by application of activated macrophage suspension

Cited by 27 publications

References 47 publications

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Rapid Recruitment and Activation of Macrophages by Anti-Gal/α-Gal Liposome Interaction Accelerates Wound Healing

Characterization of a preclinical model of chronic ischemic wound

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