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Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model.

Publication ,  Journal Article
Sergesketter, AR; Cason, RW; Ibrahim, MM; Lane, WO; Lubkin, DT; Hollenbeck, ST; Brown, DA
Published in: Plast Reconstr Surg
April 2019

BACKGROUND: The hypoxia-inducible factor (HIF) pathway, regulated by prolyl hydroxylase, is central to tissue adaptation to ischemia. The authors tested whether the prolyl hydroxylase inhibitor dimethyloxalylglycine reduces skin flap necrosis. METHODS: Dorsal skin flaps were raised on hairless rats, with dimethyloxalylglycine delivered intraperitoneally and/or topically for 7 days before and after surgery. After 14 treatment days, percentage of flap necrosis was compared grossly and tissue perfusion compared with an in vivo imaging system. Angiogenesis was compared using immunohistochemical CD31 staining and enzyme-linked immunosorbent assay for tissue vascular endothelial growth factor. Expression levels of HIF-1α and terminal deoxynucleotidyl transferase-mediated dUDP end-labeling were compared using immunohistochemical staining. Complete blood counts and gross necropsy specimens were obtained to assess systemic toxicity. RESULTS: Dimethyloxalylglycine administration significantly improved postoperative flap viability, with combined topical and intraperitoneal dimethyloxalylglycine administration leading to reduced necrosis on postsurgical day 7 at 6 mg/kg/day, 12 mg/kg/day, 24 mg/kg/day, and 48 mg/kg/day versus controls (all p < 0.05). Compared with controls (unperfused, 39.9 ± 3.8 percent), dimethyloxalylglycine treatment led to a dose-dependent decrease in unperfused tissue at 6 mg/kg/day (11.4 ± 1.7 percent), 12 mg/kg/day (9.4 ± 4.2 percent), 24 mg/kg/day (4.7 ± 2.6 percent), and 48 mg/kg/day (1.4 ± 0.9 percent) (all p < 0.001). Topical dimethyloxalylglycine application alone administered at 48 mg/kg/day was sufficient to improve flap viability (p = 0.005). Dimethyloxalylglycine-treated flaps exhibited higher CD31 staining (p = 0.004), tissue vascular endothelial growth factor (p = 0.007), HIF-1α staining (p < 0.001), and reduced terminal deoxynucleotidyl transferase-mediated dUDP end-labeling staining (p = 0.045). There were no differences in hematocrit or macroscopic organ changes on gross necropsy. CONCLUSION: Topical and systemic targeting of the HIF-1 pathway may be a promising therapeutic approach to improve flap resistance to ischemia.

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Published In

Plast Reconstr Surg

DOI

EISSN

1529-4242

Publication Date

April 2019

Volume

143

Issue

4

Start / End Page

769e / 779e

Location

United States

Related Subject Headings

  • Surgical Flaps
  • Surgery
  • Skin Transplantation
  • Skin
  • Rats, Hairless
  • Prolyl-Hydroxylase Inhibitors
  • Preoperative Period
  • Necrosis
  • Male
  • Ischemic Preconditioning
 

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Sergesketter, A. R., Cason, R. W., Ibrahim, M. M., Lane, W. O., Lubkin, D. T., Hollenbeck, S. T., & Brown, D. A. (2019). Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model. Plast Reconstr Surg, 143(4), 769e-779e. https://doi.org/10.1097/PRS.0000000000005441
Sergesketter, Amanda R., Roger W. Cason, Mohamed M. Ibrahim, Whitney O. Lane, David T. Lubkin, Scott T. Hollenbeck, and David A. Brown. “Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model.Plast Reconstr Surg 143, no. 4 (April 2019): 769e-779e. https://doi.org/10.1097/PRS.0000000000005441.
Sergesketter AR, Cason RW, Ibrahim MM, Lane WO, Lubkin DT, Hollenbeck ST, et al. Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model. Plast Reconstr Surg. 2019 Apr;143(4):769e-779e.
Sergesketter, Amanda R., et al. “Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model.Plast Reconstr Surg, vol. 143, no. 4, Apr. 2019, pp. 769e-779e. Pubmed, doi:10.1097/PRS.0000000000005441.
Sergesketter AR, Cason RW, Ibrahim MM, Lane WO, Lubkin DT, Hollenbeck ST, Brown DA. Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model. Plast Reconstr Surg. 2019 Apr;143(4):769e-779e.

Published In

Plast Reconstr Surg

DOI

EISSN

1529-4242

Publication Date

April 2019

Volume

143

Issue

4

Start / End Page

769e / 779e

Location

United States

Related Subject Headings

  • Surgical Flaps
  • Surgery
  • Skin Transplantation
  • Skin
  • Rats, Hairless
  • Prolyl-Hydroxylase Inhibitors
  • Preoperative Period
  • Necrosis
  • Male
  • Ischemic Preconditioning