Activated protein C reduces intestinal injury in an experimental model of necrotizing enterocolitis

Kumral, Abdullah; Yesilirmak, Didem Cemile; Tugyan, Kazim; Baskın, Hüseyin; Tekman, Isil; Duman, Nuray; Özkan, Hasan

doi:10.1016/j.jpedsurg.2009.07.077

Cited by 16 publications

(8 citation statements)

References 39 publications

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“…The exact mechanism of Solulin-mediated protection of radiation damage to the intestine requires further investigation, particularly with regard to the contribution of APC. A number of studies demonstrate that APC administration reduces injury and improves functional activities in various animal models of intestinal toxicity (37,56,57). On the other hand, we did not observe reduction of intestinal injury in mice when APC was administered 24 h after acute totalbody irradiation (8).…”

Section: Discussionmentioning

confidence: 99%

Radiation-Induced Activation of TGF-β Signaling Pathways in Relation to Vascular Damage in Mouse Kidneys

et al. 2009

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Section: Discussionmentioning

confidence: 99%

Radiation-Induced Activation of TGF-β Signaling Pathways in Relation to Vascular Damage in Mouse Kidneys

et al. 2009

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“…Interestingly, biopsies taken immediately adjacent to chronic wounds in patients with diabetes exhibit very low total PC (PC plus APC) levels compared to normal skin [9]. In animal models, APC is neuroprotective after stroke onset [10], protects diabetic nephropathy [11], significantly inhibits the development of lung fibrosis in bleomycin-induced lung injury [12], reduces intestinal injury in necrotizing enterocolitis [13], and accelerates healing in streptozotocin-induced diabetic rats [14]. In vitro, APC modulates keratinocyte and endothelial function towards a phenotype necessary to promote wound healing by enhancing reepithelialisation and angiogenesis [15–17].…”

Section: Introductionmentioning

confidence: 99%

Low Circulating Protein C Levels Are Associated with Lower Leg Ulcers in Patients with Diabetes

Whitmont

Fulcher

Reid

et al. 2013

BioMed Research International

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Activated protein C (APC) promotes angiogenesis and reepithelialisation and accelerates healing of diabetic ulcers. The aim of this study was to determine the relationship between the incidence of lower leg ulcers and plasma levels of APC's precursor, protein C (PC), in diabetic patients. Patients with diabetes who had a lower leg ulcer(s) for >6 months (n = 36) were compared with age-, type of diabetes-, and sex-matched subjects with diabetes but without an ulcer (n = 36, controls). Total PC was assessed using a routine PC colorimetric assay. There was a significantly (P < 0.001) lower level of plasma PC in patients with ulcers (103.3 ± 22.7, mean ± SD) compared with control (127.1 ± 34.0) subjects, when corrected for age and matched for gender and type of diabetes. Ulcer type (neuropathic, ischaemic, or mixed) was not a significant covariate for plasma PC levels (P = 0.35). There was no correlation between PC levels and gender, type of diabetes, HbA1c, or C-reactive protein in either group. In summary, decreased circulating PC levels are associated with, and may predispose to, lower leg ulceration in patients with diabetes.

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“…6 In animal models, APC is neuroprotective 4 hours after stroke onset, 7 protects diabetic nephropathy, 8 inhibits the development of lung fibrosis in bleomycin-induced lung injury, 9 and reduces intestinal injury in necrotizing enterocolitis. 10 In vitro, APC modulates keratinocyte and endothelial function, promoting wound healing by enhancing re-epithelialization and angiogenesis. [11][12][13] On the basis of in vivo and in vitro studies, 2,[11][12][13][14] one paradigm for the signaling of APC in keratinocytes and endothelial cells is explained by its binding to endothelial cell protein C receptor (EPCR) 15 and subsequent proteolytic cleavage and activation of the G proteincoupled receptor, protease activated receptor (PAR)-1, commonly referred to as the thrombin receptor.…”

mentioning

confidence: 99%

Protease Activated Receptor-2 Mediates Activated Protein C–Induced Cutaneous Wound Healing via Inhibition of p38

Julovi

Xue

Dervish

et al. 2011

The American Journal of Pathology

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Activated protein C (APC) is a natural anticoagulant that exerts anti-inflammatory and cytoprotective properties mediated through the protease activated receptor (PAR)-1. APC can also proteolytically cleave PAR-2, although subsequent function is unknown. On the basis of recent evidence that APC promotes wound healing, the aim of this study was to determine whether APC acts through PARs to heal murine excisional wounds or to regulate human cultured keratinocyte function and to determine the signaling mechanisms. Topical administration of APC accelerated wound healing in wild-type mice and, unexpectedly, in PAR-1 knockout mice. PAR-2 knockout mice healed significantly slower than wildtype mice, and healing was not altered by adding APC, indicating that APC acts through PAR-2 to heal wounds. In cultured human primary keratinocytes, APC enhanced PAR-2, stimulated proliferation, activated phosphatidylinositol 3-kinase/Src/Akt, and inhibited phosphorylated (P)-p38. Inhibiting PAR-1 or PAR-2, by small-interfering RNA or blocking antibody, reversed APC-induced keratinocyte proliferation and Akt activation. Blocking PAR-2, but not PAR-1, reversed the inhibition of P-p38 by APC. Furthermore, inhibition of P-p38 accelerated wound healing in wild-type mice. In summary, although APC acts through both PAR-1 and PAR-2 to activate Akt and to increase keratinocyte proliferation, APC-induced murine wound healing depends on PAR-2 activity and inhibition of P-p38.

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Activated protein C reduces intestinal injury in an experimental model of necrotizing enterocolitis

Cited by 16 publications

References 39 publications

Radiation-Induced Activation of TGF-β Signaling Pathways in Relation to Vascular Damage in Mouse Kidneys

Radiation-Induced Activation of TGF-β Signaling Pathways in Relation to Vascular Damage in Mouse Kidneys

Low Circulating Protein C Levels Are Associated with Lower Leg Ulcers in Patients with Diabetes

Protease Activated Receptor-2 Mediates Activated Protein C–Induced Cutaneous Wound Healing via Inhibition of p38

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