The Effect of Microporous Polysaccharide Hemospheres on Wound Healing and Scarring in Wild-Type and db/db Mice

2017 ◽  
Vol 30 (4) ◽  
pp. 169-180 ◽  
Author(s):  
Kyle J. Miller ◽  
Wei Cao ◽  
Mohamed M. Ibrahim ◽  
Howard Levinson
Keyword(s):  
Wound Healing ◽  
Wild Type ◽  
Microporous Polysaccharide Hemospheres

Impaired wound healing in embryonic and adult mice lacking vimentin

2000 ◽  
Vol 113 (13) ◽  
pp. 2455-2462 ◽  
Author(s):  
B. Eckes ◽  
E. Colucci-Guyon ◽  
H. Smola ◽  
S. Nodder ◽  
C. Babinet ◽  
...  
Keyword(s):  
Wound Healing ◽  
Healing Process ◽  
Wild Type ◽  
Impaired Wound Healing ◽  
Wound Site ◽  
Adult Mice ◽  
Tractional Forces ◽  
Filament Network ◽  
Vimentin Intermediate Filament

It is generally assumed that the vimentin intermediate filament network present in most mesenchymally-derived cells is in part responsible for the strength and integrity of these cells, and necessary for any tissue movements that require the generation of significant tractional forces. Surprisingly, we have shown that transgenic KO mice deficient for vimentin are apparently able to undergo embryonic development absolutely normally and go onto develop into adulthood and breed without showing any obvious phenotype. However, fibroblasts derived from these mice are mechanically weak and severely disabled in their capacity to migrate and to contract a 3-D collagen network. To assess whether these functions are necessary for more challenging tissue movements such as those driving in vivo tissue repair processes, we have analysed wound healing ability in wild-type versus vimentin-deficient embryos and adult mice. Wounds in vimentin-deficient adult animals showed delayed migration of fibroblasts into the wound site and subsequently retarded contraction that correlated with a delayed appearance of myofibroblasts at the wound site. Wounds made to vimentin-deficient embryos also failed to heal during the 24 hour culture period it takes for wild-type embryos to fully heal an equivalent wound. By DiI marking the wound mesenchyme and following its fate during the healing process we showed that this impaired healing is almost entirely due to a failure of mesenchymal contraction at the embryonic wound site. These observations reveal an in vivo phenotype for the vimentin-deficient mouse, and challenge the dogma that key morphogenetic events occurring during development require generation of significant tractional forces by mesenchymal cells.

scholarly journals The Vitamin D Receptor Regulates Tissue Resident Macrophage Response to Injury

Endocrinology ◽  
2016 ◽  
Vol 157 (10) ◽  
pp. 4066-4075 ◽  
Author(s):  
Lige Song ◽  
Garyfallia Papaioannou ◽  
Hengguang Zhao ◽  
Hilary F. Luderer ◽  
Christine Miller ◽  
...  
Keyword(s):  
Vitamin D ◽  
Wound Healing ◽  
Vitamin D Receptor ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Dermal Fibroblasts ◽  
Wild Type ◽  
Macrophage Response ◽  
Protein Levels ◽  
Inflammatory Phase

Ligand-dependent actions of the vitamin D receptor (VDR) play a pleiotropic role in the regulation of innate and adaptive immunity. The liganded VDR is required for recruitment of macrophages during the inflammatory phase of cutaneous wound healing. Although the number of macrophages in the granulation tissue 2 days after wounding is markedly reduced in VDR knockout (KO) compared with wild-type mice, VDR ablation does not alter macrophage polarization. Parabiosis studies demonstrate that circulatory chimerism with wild-type mice is unable to rescue the macrophage defect in the wounds of VDR KO mice and reveal that wound macrophages are of local origin, regardless of VDR status. Wound cytokine analyses demonstrated a decrease in macrophage colony-stimulating factor (M-CSF) protein levels in VDR KO mice. Consistent with this, induction of M-CSF gene expression by TGFβ and 1,25-dihydroxyvitamin D was impaired in dermal fibroblasts isolated from VDR KO mice. Because M-CSF is important for macrophage self-renewal, studies were performed to evaluate the response of tissue resident macrophages to this cytokine. A decrease in M-CSF induced proliferation and cyclin D1 expression was observed in peritoneal resident macrophages isolated from VDR KO mice, suggesting an intrinsic macrophage abnormality. Consistent with this, wound-healing assays in mice with macrophage-specific VDR ablation demonstrate that a normal wound microenvironment cannot compensate for the absence of the VDR in macrophages and thus confirm a critical role for the macrophage VDR in the inflammatory response to injury.

scholarly journals Itaconate controls the severity of pulmonary fibrosis

2020 ◽  
Vol 5 (52) ◽  
pp. eabc1884 ◽  
Author(s):  
Patricia P. Ogger ◽  
Gesa J. Albers ◽  
Richard J. Hewitt ◽  
Brendan J. O’Sullivan ◽  
Joseph E. Powell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Therapeutic Strategy ◽  
Lung Fibroblasts ◽  
Disease Phenotype ◽  
Wild Type

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1−/− mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1−/− tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

Matrix metalloproteinases 9 and 14 polymorphisms and long-term complications in surgically treated breast cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e24074-e24074
Author(s):  
Nikola Besic ◽  
Katja Goricar ◽  
Petra Piber ◽  
Neza Vavpetic ◽  
Vita Dolzan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Wound Healing ◽  
Neuropathic Pain ◽  
Matrix Metalloproteinases ◽  
Cancer Patients ◽  
Breast Cancer Surgery ◽  
Breast Cancer Patients ◽  
Wild Type ◽  
Matrix Metalloproteinases 9

e24074 Background: Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases that are involved in tissue remodeling. They can regulate interactions of cells with extracellular matrix and can play a role in wound healing. High levels of metalloproteinases have been correlated with significantly delayed wound healing in wounds of a variety of etiologies. The aim of our present study was to evaluate the association of MMP9 and MMP14 genetic polymorphisms with long-term complications of surgical treatment in breast cancer patients. Methods: The study included 99 breast cancer patients treated with either 75 or 37.5 mg of tramadol for pain relief after axillary breast cancer surgery as part of a randomized clinical trial KCT 04/2015-DORETAonko/si at Institute of Oncology Ljubljana. All patients were genotyped for MMP9 polymorphisms rs2250889, rs17577, rs17576, and rs20544 as well as MMP14 rs1042703, rs1042704, and rs743257. The association of genetic factors with long-term complications was evaluated using logistic regression. Results: One year after surgery, 24 (24.2%) patients had lymphedema, 25 (25.3%) experienced neuropathic pain and 21 (21.1%) experienced chronic pain. Carriers of polymorphic MMP9 rs2250889 allele experienced significantly more lymphedema compared to carriers of two wild-type alleles (OR = 3.45, 95% CI = 1.10-10.84, P = 0.034), even after adjustment for tramadol dose (OR = 3.76, 95% CI = 1.16-12.18, P = 0.027). Carriers of polymorphic MMP14 rs1042704 allele experienced more neuropathic pain compared to carriers of two wild-type alleles (OR = 3.21, 95% CI = 1.26-8.20, P = 0.015), even after adjustment for tramadol dose (OR = 3.80, 95% CI = 1.42-10.17, P = 0.008). Conclusions: MMP genetic variability was associated with long-term complications after axillary surgery in breast cancer patients, suggesting that MMPs may have an important role as modulators of wound healing.

Restoring Initial Thrombin Generation Does Not Normalize Cutaneous Wound Healing in Hemophilia B.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1030-1030
Author(s):  
Anna G. McDonald ◽  
Maureane Hoffman ◽  
Ulla Hedner ◽  
Harold R. Roberts ◽  
Dougald M. Monroe
Keyword(s):  
Wound Healing ◽  
Mouse Model ◽  
Thrombin Generation ◽  
Hemophilia B ◽  
Cutaneous Wound Healing ◽  
Wild Type ◽  
Cutaneous Wound ◽  
Time Points ◽  
B Mice ◽  
Hemophilia B Mouse

Abstract We recently described abnormal wound healing in a mouse model of hemophilia B (Hoffman et al, Blood 2006; DOI 10.1182/blood-2006-05-020495). Specifically: epithelial closure was delayed in hemophilia B mice; hemophilic animals, unlike wild type, developed subcutaneous hematomas; macrophage influx was delayed compared to wild-type mice; and, surprisingly, angiogenesis was enhanced in the hemophilia B mice. We hypothesized that restoring the initial hemostatic burst of thrombin generation following wounding by administration of a single dose of factor IX (FIX) replacement or factor VIIa (FVIIa) bypassing therapy would not only prevent bleeding, but correct the subsequent wound healing process. One dose of therapy was given thirty minutes prior to placement of a single three mm punch biopsy wound on the dorsal skin of each wild type, untreated hemophilia B, and treated hemophilia B mouse. The size of the wounds was measured daily until full epithelial closure. The time course of epithelial closure in treated hemophilia B was intermediate between wild type and untreated hemophilia B. FVIIa-treated hemophilia B began to heal earlier than FIX-treated. Skin from the wound site was collected at different days and examined histologically. Macrophage influx was earlier in treated hemophilia B mice compared to untreated hemophilia B, likely a due to the increased thrombin and fibrin acting as chemotactic agents. The macrophage influx in FVIIa-treated HB was significantly greater at certain time points than in FIX-treated mice, possibly reflecting some signaling effect of TF/FVIIa in addition to its effects on thrombin generation. With the earlier influx in macrophages, hemoglobin was degraded to storage iron at earlier time points. However, tissue iron continued to persist in treated hemophilia B mice similar to untreated hemophilia B, suggesting continued rebleeding. FIX treatment led to significantly more angiogenesis than FVIIa. The reasons for this difference remain to be determined. Untreated and some treated hemophilia B mice developed subcutaneous hematomas both before and after wound closure. The early hematomas are likely caused by a combination of the initial wounding trauma and vulnerability to bleeding related to the high level of vascularity within the granulation tissue. We propose the late hematomas are due to a cycle of bleeding, leading to more inflammation with production of more pro-angiogenic cytokines, leading to greater angiogenesis with its attendant risk of bleeding. In conclusion, restoring initial hemostatic thrombin generation did not normalize cutaneous wound healing in a hemophilia B mouse model. While the time frame of healing may not be the same in human and murine hemophiliacs, our findings suggest that this model could be helpful in rational determination of treatment schedules for replacement or bypassing therapy following injury or surgery.

scholarly journals LDL induces cholesterol loading and inhibits endothelial proliferation and angiogenesis in Matrigels: correlation with impaired angiogenesis during wound healing

2020 ◽  
Vol 318 (4) ◽  
pp. C762-C776
Author(s):  
Yedida Y. Bogachkov ◽  
Lin Chen ◽  
Elizabeth Le Master ◽  
Ibra S. Fancher ◽  
Yan Zhao ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Wound Healing ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Lipid Order ◽  
Endothelial Proliferation ◽  
Skin Punch Biopsy ◽  
Endothelial Growth Factor

Hypercholesterolemia is a major risk factor for adverse cardiovascular outcomes, but its effect on angiogenesis and wound healing is not well understood. In this study, using a combination of mass spectrometry and laurdan two-photon imaging, we show that elevated levels of low-density lipoprotein (LDL), like those seen in hypercholesterolemic patients, lead to an increase in both free cholesterol and cholesterol esters, as well as increase in lipid order of endothelial cell membranes. Notably, these effects are distinct and opposite to the lack of cholesterol loading and the disruption of lipid order observed in our earlier studies in response to oxidized LDL (oxLDL). The same pathological level of LDL leads to a significant inhibition of endothelial proliferation and cell cycle arrest in G2/M phase, whereas oxLDL enhances endothelial proliferation in S phase of the cycle. LDL but not oxLDL suppresses the expression of vascular endothelial growth factor receptor-2 while enhancing the expression of vascular endothelial growth factor (VEGF). Furthermore, we show that aged (8–10 mo) hypercholesterolemic apolipoprotein E-deficient (ApoE−/−) mice display delayed wound closure compared with age-matched C57/BL6 wild-type controls following a skin punch biopsy. The delay in wound healing is associated with a decreased expression of cluster of differentiation 31 platelet endothelial cell adhesion molecule endothelial marker and decreased angiogenesis within the wound bed. Furthermore, decreased endothelial responsiveness to the growth factors VEGF and basic fibroblast growth factor is observed in ApoE−/− mice in Matrigel plugs and in Matrigels with high levels of LDL in wild-type mice. We propose that plasma hypercholesterolemia is antiangiogenic due to elevated levels of LDL.

scholarly journals The interaction of ceramide 1-phosphate with group IVA cytosolic phospholipase A2 coordinates acute wound healing and repair

2019 ◽  
Vol 12 (610) ◽  
pp. eaav5918 ◽  
Author(s):  
H. Patrick MacKnight ◽  
Daniel J. Stephenson ◽  
L. Alexis Hoeferlin ◽  
Savannah D. Benusa ◽  
James T. DeLigio ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Repair ◽  
Dermal Fibroblasts ◽  
Mutant Form ◽  
Collagen Deposition ◽  
Wild Type ◽  
Fibroblast Migration ◽  
Cytosolic Phospholipase ◽  
Group Iva ◽  
Ceramide 1

The sphingolipid ceramide 1-phosphate (C1P) directly binds to and activates group IVA cytosolic phospholipase A2 (cPLA2α) to stimulate the production of eicosanoids. Because eicosanoids are important in wound healing, we examined the repair of skin wounds in knockout (KO) mice lacking cPLA2α and in knock-in (KI) mice in which endogenous cPLA2α was replaced with a mutant form having an ablated C1P interaction site. Wound closure rate was not affected in the KO or KI mice, but wound maturation was enhanced in the KI mice compared to that in wild-type controls. Wounds in KI mice displayed increased infiltration of dermal fibroblasts into the wound environment, increased wound tensile strength, and a higher ratio of type I:type III collagen. In vitro, primary dermal fibroblasts (pDFs) from KI mice showed substantially increased collagen deposition and migration velocity compared to pDFs from wild-type and KO mice. KI mice also showed an altered eicosanoid profile of reduced proinflammatory prostaglandins (PGE2 and TXB2) and an increased abundance of certain hydroxyeicosatetraenoic acid (HETE) species. Specifically, an increase in 5-HETE enhanced dermal fibroblast migration and collagen deposition. This gain-of-function role for the mutant cPLA2α was also linked to the relocalization of cPLA2α and 5-HETE biosynthetic enzymes to the cytoplasm and cytoplasmic vesicles. These findings demonstrate the regulation of key wound-healing mechanisms in vivo by a defined protein-lipid interaction and provide insights into the roles that cPLA2α and eicosanoids play in orchestrating wound repair.

scholarly journals Zyxin Mediates Vascular Repair via Endothelial Migration Promoted by Forskolin in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuya Kang ◽  
Yanan Deng ◽  
Yang Cao ◽  
Yingqing Huo ◽  
Jincai Luo
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Carotid Artery ◽  
Vascular Injury ◽  
Camp Signaling ◽  
Blue Staining ◽  
Wild Type ◽  
Wound Healing Assay ◽  
Endothelial Repair ◽  
Endothelial Migration

Background and Purpose: Endothelial repair upon vascular injury is critical for the protection of vessel integrity and prevention of the development of vascular disorders, but the underlying mechanisms remain poorly understood. In this study, we investigated the role of zyxin and its associated cyclic adenosine monophosphate (cAMP) signaling in the regulation of re-endothelialization after vascular injury.Experimental Approach: In zyxin-/- and wild-type mice, wire injury of the carotid artery was carried out, followed by Evans blue staining, to evaluate the re-endothelialization. Mice with endothelium-specific zyxin knockout were used to further determine its role. An in vitro wound-healing assay was performed in primary human endothelial cells (ECs) expressing zyxin-specific short-hairpin RNAs (shRNAs) or scrambled controls by measuring cell migration and proliferation. The effects of the cAMP signaling agonist forskolin were assessed.Key Results: The re-endothelialization of the injured carotid artery was impaired in zyxin-deficient mice, whereas the rate of cell proliferation was comparable with that in wild-type controls. Furthermore, endothelium-specific deletion of zyxin led to similar phenotypes. Knockdown of zyxin by shRNAs in primary human ECs significantly reduced cell migration in the wound-healing assay. Notably, forskolin enhanced endothelial migration in a dose-dependent manner, and this was dependent on zyxin through its interaction with vasodilator-stimulated phosphoprotein. In addition, forskolin promoted the re-endothelialization of the injured carotid artery, and this was compromised by zyxin deficiency.Conclusion and Implications: This study reveals zyxin as a new player in endothelial repair, which is promoted by forskolin, after vascular injury. Thus, zyxin-mediated signaling might be a potential treatment target for diseases involving vascular injury.

scholarly journals Syndecan-4–dependent Rac1 regulation determines directional migration in response to the extracellular matrix

2007 ◽  
Vol 177 (3) ◽  
pp. 527-538 ◽  
Author(s):  
Mark D. Bass ◽  
Kirsty A. Roach ◽  
Mark R. Morgan ◽  
Zohreh Mostafavi-Pour ◽  
Tobias Schoen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Leading Edge ◽  
Migratory Behavior ◽  
Membrane Protrusion ◽  
Wild Type ◽  
Directional Migration ◽  
Rac1 Activity ◽  
The Matrix ◽  
Protein Kinase Cα

Cell migration in wound healing and disease is critically dependent on integration with the extracellular matrix, but the receptors that couple matrix topography to migratory behavior remain obscure. Using nano-engineered fibronectin surfaces and cell-derived matrices, we identify syndecan-4 as a key signaling receptor determining directional migration. In wild-type fibroblasts, syndecan-4 mediates the matrix-induced protein kinase Cα (PKCα)–dependent activation of Rac1 and localizes Rac1 activity and membrane protrusion to the leading edge of the cell, resulting in persistent migration. In contrast, syndecan-4–null fibroblasts migrate randomly as a result of high delocalized Rac1 activity, whereas cells expressing a syndecan-4 cytodomain mutant deficient in PKCα regulation fail to localize active Rac1 to points of matrix engagement and consequently fail to recognize and respond to topographical changes in the matrix.

Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction

2006 ◽  
Vol 290 (1) ◽  
pp. H232-H239 ◽  
Author(s):  
Merry L. Lindsey ◽  
G. Patricia Escobar ◽  
Lawrence W. Dobrucki ◽  
Danielle K. Goshorn ◽  
Shenikqua Bouges ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Wound Healing ◽  
Blood Vessel ◽  
Gene Deletion ◽  
Left Ventricular ◽  
Wild Type ◽  
Angiogenic Response ◽  
Postmyocardial Infarction ◽  
Metalloproteinase 9

Matrix metalloproteinases (MMPs) are postulated to be necessary for neovascularization during wound healing. MMP-9 deletion alters remodeling postmyocardial infarction (post-MI), but whether and to what degree MMP-9 affects neovascularization post-MI is unknown. Neovascularization was evaluated in wild-type (WT; n = 63) and MMP-9 null ( n = 55) mice at 7-days post-MI. Despite similar infarct sizes, MMP-9 deletion improved left ventricular function as evaluated by hemodynamic analysis. Blood vessel quantity and quality were evaluated by three independent studies. First, vessel density was increased in the infarct of MMP-9 null mice compared with WT, as quantified by Griffonia ( Bandeiraea) simplicifolia lectin I (GSL-I) immunohistochemistry. Second, preexisting vessels, stained in vivo with FITC-labeled GSL-I pre-MI, were present in the viable but not MI region. Third, a technetium-99m-labeled peptide (NC100692), which selectively binds to activated αvβ3-integrin in angiogenic vessels, was injected into post-MI mice. Relative NC100692 activity in myocardial segments with diminished perfusion (0–40% nonischemic) was higher in MMP-9 null than in WT mice (383 ± 162% vs. 250 ± 118%, respectively; P = 0.002). The unique finding of this study was that MMP-9 deletion stimulated, rather than impaired, neovascularization in remodeling myocardium. Thus targeted strategies to inhibit MMP-9 early post-MI will likely not impair the angiogenic response.

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