Prolonged Inflammatory Phase Research Articles

Angiotensin-(1-7) oral treatment after experimental myocardial infarction leads to downregulation of CXCR4

Myocardial infarction triggers cellular events that starts with the activation of inflammatory response and fibrogenic pathways involved in cardiac tissue remodeling. Angiotensin-(1–7) (Ang-(1–7)) is an endogenous heptapeptide from the renin-angiotensin system with a cardioprotective role due to its anti-inflammatory and anti-fibrotic activities in cardiac cells. Although the beneficial aspects of Ang-(1–7) in animal models of cardiac ischemia have been reported, the molecular events underlying Ang-(1–7) cardioprotective effect remains elusive. This study investigated the impact of oral treatment with Ang-(1–7) included in hydroxypropyl β-cyclodextrin (HPβCD/Ang-(1–7)) on the cardiac proteome dysregulation due to experimental myocardial infarction. Wistar male rats were submitted to experimental myocardial infarction and treated daily with HPβCD/Ang-(1–7) during 7 days or 60 days by gavage. Our results showed that HPβCD/Ang-(1–7) treatment ameliorates the post-infarction condition due to the modulation of proteins that initially favor the resolution of inflammation and mitochondrial dysfunction. Moreover, this study reported for the first time that Ang-(1–7) treatment after experimental myocardial infarction leads to the downregulation of the C-X-C chemokine receptor type 4 (CXCR4). SignificanceMyocardial infarction triggers a sequence of cellular and molecular events that starts with an intense inflammatory response that is resolved in the proliferative phase. Prolonged inflammatory phase can lead to adverse cardiac repair and heart failure. In this context, we proposed a post-MI treatment using Ang-(1–7) included in HPβCD and administrated orally. We observed that HPβCD/Ang-(1–7) treatment led to CXCR4 downregulation, highlighting this C-X-C chemokine receptor as a potential therapeutic target for ischemic heart diseases.

Is leukotriene B4 one of the keloid marker? a fibroblast keloid study

Keloid pathogenesis occurs due to the duration of prolonged inflammatory phase and increased production of various growth factors such as TGF-β1 which may cause increasing fibroblast proliferation and collagen synthesis. Existence of one of the chemical mediators released during inflammation, leukotriene B4 (LTB4), in keloid pathogenesis specifically in the phases of inflammation and proliferation, is still unclear. The purpose of the study is to analyze the levels of LTB4 in keloid. Methods: Fibroblast culture that was done by explanting keloid and normal skin of a keloid patient. Measurement of LTB4 on keloid and normal fibroblast was done by Elisa method. This experiment was run in triplicate. Statistical test was conducted by t test for the unpaired data and Anova test. The experiment was done at cell culture laboratory of Medical Faculty of Padjadjaran University Bandung. Levels of LTB4 in keloid fibroblast was higher than that of normal skin fibroblast (mean 23143.27 vs 18191.85 pg/ml; p<0.05). Conclusion, increased LTB4 levels in keloid fibroblast showed the existence of LTB4 role in the prolonged inflammatory process in keloid pathogenesis.

A study on wound asepsis score for skin closure in surgical procedures

Acute wounds progress through the phases in an orderly fashion for normal healing to occur. Chronic wounds begin the healing process in a similar fashion; however, they have prolonged inflammatory phase in which there is significant destruction of the matrix elements caused by the release of proteolytic enzymes from the neutrophils. This was a comparative study in which patients were studied in two groups. One group comprised of incision closure with subcuticular 3-0 polyamide suture material and the other group comprised of closure with 2 - octylcyanoacrylate adhesive glue. The ASEPSIS score on 5th day shows a mean score of 0.12 for the adhesive glue group and a mean score of 0.28 for subcuticular skin suturing group (P=0.4). Here again there is a numerical difference in favor of adhesive glue group which n is statistically insignificant.

Flexible agar-sericin hydrogel film dressing for chronic wounds

Chronic wounds suffer impaired healing that results in psychological effect and morbity in addition to economic burden on the patient. These wounds are characterized by prolonged inflammatory phase, poor collagen production, hampered angiogenesis, upregulation in reactive oxygen species (ROS) and matrix metalloproteases (MMP). In the current work, three different concentrations (03:01, 05:01 and 10:01) of flexible agar-sericin-glycerol hydrogel films with sericin as minor component were fabricated to improve collagen production and capture free radical species to expediate chronic wound healing. The films exhibited improved collagen production with a p-value ≤ 0.001 for all the three concentrations. With regards to free radical scavenging, the 03:01 and 05:01 films exhibited improved performance with a p-value ≤ 0.01, while, 10:01 film showed improvement with a p-value ≤ 0.05. This was confirmed by Sirius red staining and 2,2-diphenyl-1-picryl hydrazyl (DPPH) assay. In addition, these films showed an adequate tensile strength of around 35 MPa with elongation at break higher than 25%. The as cast films exhibited satisfactory swelling behavior of around 320% in simulated wound fluid (SWF).

Comparison of the Local Tolerability to 5 Long-acting Drug Nanosuspensions with Different Stabilizing Excipients, Following a Single Intramuscular Administration in the Rat

To investigate the effects of common nanosuspension-stabilizing excipients on the nature and temporal evolution of histopathological changes at intramuscular (i.m.) administration sites, 5 groups of 39 male rats per group received a single injection of 1 of the 5 analogous crystalline drug nanosuspensions containing 200 mg/ml of an antiviral compound with particle sizes of ±200 nm and identical vehicle compositions, except for the type of nanosuspension stabilizer. The investigated stabilizers were poloxamer 338, poloxamer 407, d-α-tocopherol polyethylene glycol 1,000-succinate (TPGS), polysorbate 80, and polysorbate 80 combined with egg phosphatidylglycerol. Histopathology and immunohistochemistry revealed progressive inflammatory changes at the i.m. administration sites and the draining lymph nodes that differed according to the time point of sacrifice and the type of stabilizer. Although the overall time course of inflammatory changes was similar across the groups, differences in the nature, severity, and timing of the inflammatory response were observed between animals injected with poloxamer- or TPGS-containing nanosuspensions and those injected with formulations containing polysorbate 80. A more severe and prolonged active inflammatory phase, the presence of multinucleate giant cells, prolonged macrophage infiltration of the formulation depot, and more persistent histiocytic infiltrates in the lymph nodes were observed in the polysorbate 80-containing nanosuspension groups. Such vehicle-mediated effects could influence the overall tolerability profile of long-acting nanosuspensions.

Simultaneous silencing of TGF-β1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis.

Excessive skin scars due to elective operations or trauma represent a challenging clinical problem. Pathophysiology of hypertrophic scars entails a prolonged inflammatory and proliferative phase of wound healing. Over expression of TGF-β1 and COX-2 play key regulatory roles of the aberrant fibrogenic responses and proinflammatory mediators. When we silenced TGF-β1 and COX-2 expression simultaneously in primary human fibroblasts, a marked increase in the apoptotic cell population occurred in contrast to those only treated with either TGF-β1 or COX-2 siRNA alone. Furthermore, using human hypertrophic scar and skin graft implant models in mice, we observed significant size reductions of the implanted tissues following intra-scar administration of TGF-β1/COX-2 specific siRNA combination packaged with Histidine Lysine Polymer (HKP). Gene expression analyses of those treated tissues revealed silencing of the target gene along with down regulations of pro-fibrotic factors such as α-SMA, hydroxyproline acid, Collagen 1 and Collagen 3. Using TUNEL assay detection, we found that the human fibroblasts in the implanted tissues treated with the TGF-β1/COX-2siRNAs combination exhibited significant apoptotic activity. Therefore we conclude that a synergistic effect of the TGF-β1/COX-2siRNAs combination contributed to the size reductions of the hypertrophic scar implants, through activation of fibroblast apoptosis and re-balancing between scar tissue deposition and degradation.

Platelet-rich plasma for the treatment of chronic wounds: evidence to date

Platelet-rich plasma for the treatment of chronic wounds: evidence to date Elena Conde-Montero,1 Pablo de la Cueva Dobao,1 José María Martínez González2 1Department of Dermatology, Hospital Universitario Infanta Leonor, 2Faculty of Dentistry, Universidad Complutense de Madrid, Madrid, Spain Abstract: Platelet-rich plasma (PRP) is a widely used throughout diverse fields of medicine for improving tissue regeneration. In dermatology, its main applications in the last few years have mainly been in antiaging treatment and wound healing. PRP contains platelets at higher concentrations than whole blood, and consequently represents a growth-factor pool. Chronic wounds are characterized by a prolonged inflammatory phase, involving a continuous destruction of matrix proteins and growth factors. Growth factors promote cell migration, proliferation, and differentiation, which are essential for wound healing. In this review, we explain the basic principles of PRP in wound healing and aim to offer an updated critical assessment of the available clinical evidence that supports the utility of PRP for the therapeutic challenge that chronic ulcers represent in our daily clinical practice. Keywords: platelet-rich plasma, chronic wounds, growth factors, wound healing, platelet gel

Selective M2 Macrophage Depletion Leads to Prolonged Inflammation in Surgical Wounds

Background: A prolonged inflammatory phase is seen in aberrant wound healing and in chronic wounds. Macrophages are central to wound healing. Distinct macrophage subtypes have differing roles both in initial inflammation and in later tissue repair. Broadly, these cells can be divided into M1 and M2 macrophages. M2 macrophage proliferation and differentiation is regulated by colony-stimulating factor 1 (CSF-1) signalling and can be blocked by GW2580, a competitive cFMS kinase inhibitor, thereby allowing for analysis of the effect of M2 blockade on progression of surgical wounds. Materials and Methods: Macrophage Fas-induced apoptosis (MaFIA) transgenic mice with a macrophage-specific promoter used to express green fluorescent protein (GFP) were used to allow for cell tracking. The animals were treated by oral gavage with GW2580. Surgical wounds were created and harvested after 2 weeks for analysis. Results: GW2580-treated mice had significantly more GFP+ cells in the surgical scar than vehicle-treated animals (GW2580, 68.0 ± 3.1%; vehicle, 42.8 ± 1.7%; p < 0.001), and GW2580 treatment depleted CD206+ M2 macrophages in the scar (GW2580, 1.4%; vehicle, 19.3%; p < 0.001). Treated animals showed significantly higher numbers of neutrophils (vehicle, 18.0%; GW2580, 51.3%; p < 0.01) and M1 macrophages (vehicle, 3.8%; GW2580, 12.8%; p < 0.01) in the scar compared to vehicle-treated animals. The total collagen content in the area of the scar was decreased in animals treated with GW2580 as compared to those treated with vehicle alone (GW2580, 67.1%; vehicle, 79.9%; p < 0.005). Conclusions: Depletion of M2 macrophages in surgical wounds via CSF-1 signalling blockade leads to persistent inflammation, with an increase in neutrophils and M1 macrophages and attenuated collagen deposition.

A single-centre, retrospective study of cryopreserved umbilical cord/amniotic membrane tissue for the treatment of diabetic foot ulcers.

Histopathological studies have shown a prolonged inflammatory phase in wounds of patients with diabetes, delaying formation of mature granulation tissue and reducing wound tensile strength, making these wounds difficult for physicians to heal. Cryopreserved human umbilical cord (cUC) tissues possess unique anti-inflammatory and anti-scarring properties and have been found to help improve closure of these chronic wounds. A retrospective chart review was performed to assess the efficacy of cUC as an advanced treatment modality to help promote the closure of chronic DFUs. Overall healing rate, duration to wound closure, and number of cUC applications used to achieve closure were used to assess cUC treatment efficacy. A total of 32 wounds in 29 patients treated at a single health-care centre were included in the study population The average initial wound area for all wounds was 10.6 ± 2.15cm2. Of the 32 wounds 28 achieved complete epithelialisation for an overall healing rate of 87.5%. Average time to wound closure was 13.8 ± 1.95 weeks with a median of 9 weeks and an average of 1.68 ± 0.18 cUC applications. The results suggest cUC allograft may be effective in improving the healing of DFUs ulcers as well as potentially reducing the medical costs associated with chronic DFUs due to the low number of applications needed to achieve complete wound closure. Prospective, randomised controlled trials are suggested to better understand the efficacy of cUC in chronic wound healing. Dr Raphael is a paid speaker for Amniox Medical, Inc.

Angiogenic and Immunomodulatory Properties of Endothelial and Mesenchymal Stem Cells.

It has been suggested that the effect of implanted cells on the local environment is important when selecting the appropriate cell type for tissue regeneration. Our aim was to compare the local tissue response to implanted human mesenchymal stem cells (MSC) and human umbilical vein endothelial cells (EC). MSC and EC were cultured in poly(l-lactide-co-1,5-dioxepan-2-one) scaffolds for 1 week in a bioreactor system, after which they were implanted subcutaneously in NOD/SCID mice. After 3 weeks, scaffolds were retrieved, and the mRNA expression of selected genes involved in hypoxia and inflammation was examined by real-time reverse transcription polymerase chain reaction and correlated with immunofluorescent staining for corresponding proteins. The Toll-like receptor signaling pathway was examined by superarray hybridization. The expression of 53 angiogenesis-related proteins was investigated by a proteome profiler angiogenesis antibody array kit. Vascularization was quantified using immunohistochemistry for CD31. The expression of hypoxia-inducible factors and biomarkers for angiogenesis was more strongly upregulated in response to implanted EC than to MSC, suggesting a higher sensitivity to low oxygen tension among EC. Hypoxic signaling was increased after implantation of EC compared with MSC, leading to a prolonged acute inflammatory phase that promoted ingrowth of vascular cells and establishment of the circulation. Inflammatory cytokines were also differently expressed at the gene and protein levels in the two experimental groups, resulting in altered recruitment of acute and chronic inflammatory cells. The end result of these differences was increased vessel formation within the constructs in the EC group.

A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing.

Chronic or non-healing wounds are a major concern in clinical practice and these wounds are mostly associated with diabetes, and venous and pressure ulcers. Wound healing is a complex process involving overlapping phases and the primary phase in this complex cascade is the inflammatory state. While inflammation is necessary for wound healing, a prolonged inflammatory phase leads to impaired healing. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that are expressed in high levels under stress conditions. Recently, we demonstrated that a deficiency in CIRP led to decreased inflammation and mortality in an experimental model of hemorrhagic shock. Thus, we hypothesized that a deficiency in CIRP would accelerate the inflammatory phase and lead to an improvement in cutaneous wound healing. In this study, to examine this hypothesis, a full-thickness wound was created on the dorsum of wild-type (WT) and CIRP-/- mice. The wound size was measured every other day for 14 days. The wound area was significantly decreased in the CIRP-/- mice by day 9 and continued to decrease until day 14 compared to the WT mice. In a separate cohort, mice were sacrificed on days 3 and 7 after wounding and the skin tissues were harvested for histological analysis and RNA measurements. On day 3, the mRNA expression of tumor necrossis factor (TNF)-α in the skin tissues was increased by 16-fold in the WT mice, whereas these levels were increased by 65-fold in the CIRP-/- mice. Of note on day 7, while the levels of TNF-α remained high in the WT mice, these levels were significantly decreased in the CIRP-/- mice. The histological analysis of the wounded skin tissue indicated an improvement as early as day 3 in the CIRP-/- mice, whereas in the WT mice, infiltrated immune cells were still present on day 7. On day 7 in the CIRP-/- mice, Gr-1 expression was low and CD31 expression was high, whereas in the WT mice, Gr-1 expression was high and CD31 expression was low, indicating that the CIRP-/- mice have already moved into the angiogenesis and tissue formation phase, whereas the WT mice were still in the inflammatory state. These data collectively suggest that a deficiency in CIRP accelerates the wound healing process.

FEATURES OF WOUND PROCESS AFFECTED BY DIABETES MELLITUS

Objective – to study the morphology of wound process in diabetic patients. Materials and methods. The subjects treated in this study were 180 patients: 122 females (67.8 %) and 58 males (32.2 %). Traditional methods for evaluating the morphology of wound healing have been used: imprint smear of the edge of the wound according to the method of M.P. Pokrovskaya and M.S.Makarov (1942), staining of paraffin sections according to the histochemical methods proposed by D.D. Zerbino and L.L. Lukasevich (1984), study of epidermal thickness and its keratinization degree, measuring of the epidermal zone and dermoepidermal junction. All measurements in histological sections were carried out using the eyepiece-micrometer, the results presented in micrometers. Results. It is found that in patients with diabetes mellitus with increasing duration of the disease occurs thinning of epidermis and the signs of keratinization of the epidermis. In the zone of dermoepidermal junction and dermis in patients with diabetes mellitus there is emergence of adipose tissue. This incidence of adipose tissue correlates with the duration of the disease. The amount of regeneration-degeneration index correlates with the nature of the wound process. Conclusions. In the skin of patients with diabetes mellitus there appear symptoms of parenchymal proteinosis and adipose degeneration, which reflects metabolic imbalance in tissue. The wound process in patients suffering from diabetes mellitus is characterized by prolonged inflammatory phase and delayed regenerative processes.

Interleukin 2 Topical Cream for Treatment of Diabetic Foot Ulcer: Experiment Protocol.

BackgroundIt is estimated there are 2.9 million diabetic patients in the United Kingdom, and around 5%-7% of patients have diabetic ulcers. This number will continue to increase globally. Diabetic ulcers are a major economic burden on the healthcare system. More than £650 million is spent on foot ulcers or amputations each year, and up to 100 people a week have a limb amputated due to diabetes. In T1DM, the level of IL-2 is reduced, and hence, wound healing is in a prolonged inflammatory phase. It is not known if IL-2 topical cream can shorten the healing process in T1DM patients.ObjectiveThe objective of this study is to understand the pathophysiology in type 1 diabetes (T1DM) and investigate possible future treatment based on its clinical features. The hypothesis is that IL-2 cream can speed up wound healing in NOD mice and that this can be demonstrated in a ten-week study. An experiment protocol is designed in a mouse model for others to conduct the experiment. The discussion is purely based on diabetic conditions; lifestyle influences like smoking and drinking are not considered.MethodsSkin incisions will be created on 20 nonobese diabetic (NOD) mice, and IL-2 topical cream will be applied in a 10-week study to prove the hypothesis. Mice will be randomly and equally divide into two groups with one being the control group.ResultsT1DM patients have a decreased number of T regulatory (Treg) cells and interleukin 2 (IL-2). These are the keys to the disease progression and delay in wound healing. Diabetic ulcer is a chronic wound and characterized by a prolonged inflammatory phase.ConclusionsIf the experiment is successful, T1DM patients will have an alternative, noninvasive treatment of foot ulcers. In theory, patients with other autoimmune diseases could also use IL-2 topical cream for treatment.

Macrophage activation and its role in repair and pathology after spinal cord injury

The injured spinal cord does not heal properly. In contrast, tissue repair and functional recovery occur after skin or muscle injuries. The reason for this dichotomy in wound repair is unclear but inflammation, and specifically macrophage activation, likely plays a key role. Macrophages have the ability to promote the repair of injured tissue by regulating transitions through different phase of the healing response. In the current review we compare and contrast the healing and inflammatory responses between spinal cord injuries and tissues that undergo complete wound resolution. Through this comparison, we identify key macrophage phenotypes that are inaptly triggered or absent after spinal cord injury and discuss spinal cord stimuli that contribute to this maladaptive response. Sequential activation of classic, pro-inflammatory, M1 macrophages and alternatively activated, M2a, M2b, and M2c macrophages occurs during normal healing and facilitates transitions through the inflammatory, proliferative, and remodeling phases of repair. In contrast, in the injured spinal cord, pro-inflammatory macrophages potentiate a prolonged inflammatory phase and remodeling is not properly initiated. The desynchronized macrophage activation after spinal cord injury is reminiscent of the inflammation present in chronic, non-healing wounds. By refining the role macrophages play in spinal cord injury repair we bring to light important areas for future neuroinflammation and neurotrauma research.This article is part of a Special Issue entitled SI: Spinal cord injury.

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer.

Delayed wound healing is a major complication associated with diabetes and is a result of a complex interplay among diverse deregulated cellular parameters. Although several genes and pathways have been identified to be mediating impaired wound closure, the role of microRNAs (miRNAs) in these events is not very well understood. Here, we identify an altered miRNA signature in the prolonged inflammatory phase in a wound during diabetes, with increased infiltration of inflammatory cells in the basal layer of the epidermis. Nineteen miRNAs were downregulated in diabetic rat wounds (as compared with normal rat wound, d 7 postwounding) together with inhibited levels of the central miRNA biosynthesis enzyme, Dicer, suggesting that in wounds of diabetic rats, the decreased levels of Dicer are presumably responsible for miRNA downregulation. Compared with unwounded skin, Dicer levels were significantly upregulated 12 d postwounding in normal rats, and this result was notably absent in diabetic rats that showed impaired wound closure. In a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array, 10 genes were significantly altered in the diabetic rat wound and included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the 10 wound-healing specific genes, suggesting altered miRNAs might fine-tune the levels of these genes that determine wound closure. Dicer inhibition prevented HaCaT cell migration and affected wound closure. Altered levels of Dicer and miRNAs are critical during delayed wound closure and offer promising targets to address the issue of impaired wound healing.

Influence of a new wound-healing ointment on morphogenesis of full-thickness excision wounds in healthy rats and rats with diabetic state.

Background. Impaired wound healing is a complication of diabetic state and is a serious medical and social problem. It occurs as a consequence of disequilibrium in reactive oxygen species (ROS) and antioxidant defense system. Therefore local treatment with antioxidants is promising in this type of pathology. Objective. The aim of this study was morphological evaluation of the influence of a new wound-healing ointment containing licorice extract, coenzyme Q10 and dihydroquercetin on the model of natural and delayed wounds in rats. Methods. For morphological evaluation on Day 6 and 12 we took specimens of tissues with wound and surrounding intact skin. Prepared histological slides and stained with haematoxylin, eosin and picrofuchsin by Van Gieson. Results. It was noted that process of excision wound healing in rats with diabetic state had prolonged inflammatory phase. Thus, on the Day 6 of observation during wound-healing in a physiologically healthy rats fibrinoid-necrotic layer in the surface layers of the defect was quite dense, with a limited number of leukocyte cells. Young newly formed granulation tissue in the bottom areas also purified from neutrophil leukocytes. Inflammatory reaction in the boundary to the defect areas of skin was extinguished. And in rats with diabetic state same fibrinoid-necrotic layer was markedly attenuated, full of polymorphonuclear leukocytes, granulation cells also contained many white blood cells in the boundary areas of healthy skin observed exocytosis of epithelial layer, a marked inflammation and destruction of the dermis. All this led to decrease in speed of development and maturation of granulation tissue on the 12th day of observation in these animals compared with physiologically healthy rats. Conclusion. The results showed that the studied ointment optimizes reparative tissue regeneration in the healing of skin excision wounds in rats with pre-modeled diabetogenic state. Nature of reparative processes in these rats generally followed that of the physiologically healthy rats.

Histologic Characteristics of Vaginal Cuff Tissue From Patients With Vaginal Cuff Dehiscence

Study ObjectiveTo describe the histologic characteristics of vaginal tissue in patients with vaginal cuff dehiscence (VCD) after robotic hysterectomy and to compare this group with patients without dehiscence. DesignRetrospective analysis (Canadian Task Force classification II-3). SettingAcademic center. PatientsSeven patients with VCD and 6 patients without VCD. InterventionsVaginal cuff tissue was obtained from all patients and was stained using hematoxylin-eosin and evaluated for acute and chronic inflammation markers including neutrophils, lymphocytes, and plasma cells. Immunohistochemical staining was performed and evaluated using the semiquantitative method for collagen types I and III, smooth muscle actin, and SM22α (myofibroblast) content. Grading was performed by 4 blinded investigators. The Mann-Whitney test was used to evaluate the 2 groups, and correlation coefficients for interobserver variability. Measurements and Main ResultsThe VCD group, compared with the non-VCD group, demonstrated significantly greater numbers of neutrophils (1.71 vs 1.0; p = .04), lymphocytes (2.85 vs 1.33; p = .002), and plasma cells (2.2 vs 1.0; p = .001). There was no statistical difference between the groups in amounts of collagen I (1.71 vs 1.27; p = .09) and collagen III (1.66 vs 1.38; p = .37), smooth muscle actin (1.23 vs 1.33; p = .65), and SM22α (1.85 vs 1.27; p = .09). Interobserver variability was low (κ = 0.86; p = .76). ConclusionCompared with the control group, patients with VCD demonstrated significantly higher levels of acute and chronic inflammatory cells. This finding suggests that a prolonged inflammatory phase may be delaying normal progression to reparation in patients with dehiscence.

Xiamenmycin Attenuates Hypertrophic Scars by Suppressing Local Inflammation and the Effects of Mechanical Stress

Hypertrophic scarring is a common disease affecting millions of people around the world, but there are currently no satisfactory drugs to treat the disease. Exaggerated inflammation and mechanical stress have been shown to be two main mechanisms of excessive fibrotic diseases. Here we found that a benzopyran natural product, xiamenmycin, could significantly attenuate hypertrophic scar formation in a mechanical stretch-induced mouse model. The compound suppressed local inflammation by reducing CD4+ lymphocyte and monocyte/macrophage retention in fibrotic foci and blocked fibroblast adhesion with monocytes. Both in vivo and in vitro studies found that the compound inhibited the mechanical stress-induced profibrotic effects by suppressing proliferation, activation, fibroblast contraction, and inactivating FAK, p38, and Rho guanosine triphosphatase signaling. Taken together, the compound could simultaneously suppress both the inflammatory and mechanical stress responses, which are the two pivotal pathological processes in hypertrophic scar formation, thus suggesting that xiamenmycin can serve as a potential agent for treating hypertrophic scar formation and other excessive fibrotic diseases.

Influence of secretory leukocyte protease inhibitor‐based peptides on elastase activity and their incorporation in hyaluronic acid hydrogels for chronic wound therapy

Chronic nonhealing skin wounds, such as leg ulcers and pressure sores, represent a major clinical problem and a financial burden for the health care systems. Chronic wounds are characterized by prolonged inflammatory phase that results in high levels of elastase, reactive oxygen species (ROS), and diminished growth factor activity. Under normal physiological conditions, elastase is a powerful host defence and its activity is regulated by endogenous inhibitors. The unrestrained elastase activity in chronic wounds may be tuned by exogenous active materials that inhibit elastase. Secretory leucocyte protease inhibitor, SLPI, is a potent endogenous inhibitor of elastase. Peptide fragments, KRCCPDTCGIKCL (Pep4) and KRMMPDTMGIKML (Pep4M), selected from SLPI primary structure were studied as potential elastase inhibitors. Kinetic studies performed for human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) in presence of these peptides revealed that both behave as uncompetitive and noncompetitive inhibitors of HNE and PPE, respectively. The influence of ROS and albumin on Pep4 and Pep4M inhibitory activity toward elastase reveals that this mixture increases the inhibitory activity of both peptides. These peptides were incorporated in hyaluronic acid hydrogels to evaluate the possibility of being used as active compounds in a drug delivery system. Assessment of HNE and PPE activity in the presence of these hydrogels formulations revealed a considerable decrease in enzyme activity. Although, only moderated elastase inhibition was observed, these peptides represent potential candidates for chronic wound applications, as there is no need for complete elastase inhibition in the normal wound healing process.

Anti-inflammatory and anti-ulcer properties of hypolaetin-8-glucoside, a novel plant flavonoid.

The anti-inflammatory, analgesic and anti-ulcer activities of a novel flavonoid, hypolaetin-8-glucoside, obtained from Sideritis mugronensis, have been tested in the rat. The flavonoid was more potent than phenylbutazone in suppressing the acute phase of adjuvant-carrageenan-induced inflammation, but had less effect in the prolonged inflammatory phase. However, unlike phenylbutazone, it did not cause gastric erosions. Both compounds were equiactive in inhibiting the development of carrageenan-induced abscesses, whereas phenylbutazone had greater analgesic activity in tests on pressure pain threshold. The flavonoid and cimetidine both prevented the formation of cold-restraint induced gastric lesions, but cimetidine was more potent. These results show that hypolaetin-8-glucoside combines both anti-inflammatory and anti-ulcer properties and suggest that it may offer useful alternatives to anti-inflammatory drugs of the aspirin type.