Littérature scientifique sur le sujet « Myofibroblast MMP »

Chronic hypergastrinemia is associated with enterochromaffin-like (ECL) cell hyperplasia, which may progress to gastric carcinoid tumors. The latter consists of epithelial cells and stroma, and both compartments usually regress after normalization of hypergastrinemia. We previously showed that matrix metalloproteinase (MMP)-7 in gastric epithelial cells was upregulated by Heliobacter pylori and described MMP-7-dependent reciprocal signaling between the epithelium and a key stromal cell type, the myofibroblast. Here, we describe the regulation of gastric MMP-7 by gastrin and the potential significance for recruiting and maintaining myofibroblast populations. Biopsies of the gastric corpus and ECL cell carcinoid tumors were obtained from hypergastrinemic patients. Western blot analysis, ELISA, immunohistochemistry, and promoter-luciferase (luc) reporter assays were used to study MMP-7 expression. Gastric myofibroblasts were identified by α-smooth muscle actin (α-SMA) expression, and the effects of MMP-7 on myofibroblast proliferation were investigated. In hypergastrinemic patients, there was an increased abundance of MMP-7 and α-SMA in gastric corpus biopsies and ECL cell carcinoid tumors. In the latter, MMP-7 was localized to ECL cells but not stromal cells, which were nevertheless well represented. Gastrin stimulated MMP-7-luc expression in both AGS-GR and primary human gastric epithelial cells. Conditioned medium from gastrin-treated human gastric glands stimulated myofibroblast proliferation, which was inhibited by neutralizing antibodies to MMP-7. MMP-7 increased the proliferation of myofibroblasts via the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, stimulation of gastric MMP-7 by elevated plasma gastrin may activate epithelial-mesenchymal signaling pathways regulating myofibroblast function via MAPK and PI3K pathways and contribute to stromal deposition in ECL cell carcinoid tumors.

A prominent feature of obstructed tissue regeneration following injury in general, and fibrotic lung tissue in particular, is fibroblast proliferation and accumulation. The Fas/FasL apoptotic pathway has been shown to be involved in human idiopathic pulmonary fibrosis (IPF) and bleomycin-induced lung fibrosis in rodents. We previously showed that in normal injury repair, myofibroblasts’ accumulation is followed by their decline by FasL+ T cell-induced cell death. In pathological lung fibrosis, myofibroblasts resist cell death and accumulate. Like other members of the tumor necrosis factor (TNF) family, membrane-bound FasL can be cleaved from the cell surface to generate a soluble form (sFasL). Metalloproteinases (MMPs) are known to convert the membrane-bound form of FasL to sFasL. MMP-7 knockout (KO) mice were shown to be protected from bleomycin (BLM)-induced lung fibrosis. In this study, we detected increased levels of sFasL in their blood serum, as in the lungs of patients with IPF, and IPF-lung myofibroblast culture medium. In this study, using an MMP-inhibitor, we showed that sFasL is decreased in cultures of IPF-lung myofibroblasts and BLM-treated lung myofibroblasts, and in the blood serum of MMP-7KO mice. Moreover, resistant fibrotic-lung myofibroblasts, from the lungs of humans with IPF and of BLM-treated mice, became susceptible to T-cell induced cell death in a co-culture following MMP-inhibition- vs. control-treatment or BLM-treated MMP-7KO vs. wild-type mice, respectively. sFasL may be an unrecognized mechanism for MMP-7-mediated decreased tissue regeneration following injury and the evolution of lung fibrosis.

Vascular endothelial growth factor (VEGF)-C is a key mediator of lymphangiogenesis. Our recent study shows that VEGF-C/VEGF receptors (VEGFR)-3 are significantly increased in the infarcted rat myocardium, where VEGFR-3 is expressed not only in lymph ducts but also in myofibroblasts, indicating that VEGF-C has an unrevealed role in fibrogenesis during cardiac repair. The current study is to explore the regulation and molecular mechanisms of VEGF-C in fibrogenesis. The potential regulation of VEGF-C on myofibroblast differentiation/growth/migration, collagen degradation/synthesis, and transforming growth factor (TGF)-β and ERK pathways was detected in cultured cardiac myofibroblasts. Our results showed that VEGF-C significantly increased myofibroblast proliferation, migration, and type I/III collagen production. Matrix metalloproteinase (MMP)-2 and -9 were significantly elevated in the medium of VEGF-C-treated cells, coincident with increased tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Furthermore, VEGF-C activated the TGF-β1 pathway and ERK phosphorylation, which was significantly suppressed by TGF-β or ERK blockade. This is the first study indicating that in addition to lymphangiogenesis, VEGF-C is also involved in fibrogenesis through stimulation of myofibroblast proliferation, migration, and collagen synthesis, via activation of the TGF-β1 and ERK pathways.

Fibroblast proliferation and extracellular matrix accumulation characterize idiopathic pulmonary fibrosis (IPF). We evaluated the presence of tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4; collagenase-1, -2, and -3; gelatinases A and B; and membrane type 1 matrix metalloproteinase (MMP) in 12 IPF and 6 control lungs. TIMP-1 was found in interstitial macrophages and TIMP-2 in fibroblast foci. TIMP-3 revealed an intense staining mainly decorating the elastic lamina in vessels. TIMP-4 was expressed in IPF lungs by epithelial and plasma cells. TIMP-2 colocalized with Ki67 in fibroblasts, whereas TIMP-3 colocalized with p27 in inflammatory and epithelial cells. Collagenase-1 was localized in macrophages and alveolar epithelial cells, collagenase-2 was localized in a few neutrophils, and collagenase-3 was not detected. MMP-9 was found in neutrophils and subepithelial myofibroblasts. Myofibroblast expression of MMP-9 was corroborated in vitro by RT-PCR. MMP-2 was noticed in myofibroblasts, some of them close to areas of basement membrane disruption, and membrane type 1 MMP was noticed in interstitial macrophages. These findings suggest that in IPF there is higher expression of TIMPs compared with collagenases, supporting the hypothesis that a nondegrading fibrillar collagen microenvironment is prevailing.

Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP aactions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.

BackgroundAcacia honey is known to have antioxidant, immune-modulatory, and antiproliferative properties. Nasal fibroblasts participate in local immune responses that control the recruitment of inflammatory cells and the production of extracellular matrix.ObjectivesThe aim of this study was to determine the effect of acacia honey on myofibroblast differentiation and matrix metalloproteinase-9 (MMP-9) production in nasal polyp fibroblasts.MethodsPrimary nasal fibroblasts were isolated from nasal polyps and treated with transforming growth factor-beta 1 (TGF-β1). Reverse transcription-polymerase chain reaction and Western blot analysis were then performed to determine α-smooth muscle actin (α-SMA), tissue inhibitors of matrix metalloproteinase-1, and MMP-9 mRNA expression and protein production in nasal polyp fibroblasts. Phosphorylated Smad ( pSmad) 2/3 and phosphorylated adenosine monophosphate-activated protein kinase ( pAMPK) were then determined by Western blotting.ResultsTGF-β1 stimulation increased α-SMA and MMP-9 mRNA expression and protein production in nasal polyp fibroblasts. Acacia honey effectively suppressed α-SMA and MMP-9 mRNA expression and protein production. It also prevented phosphorylation of Smad 2/3 and AMPK.ConclusionAcacia honey can inhibit TGF-β1-induced myofibroblast differentiation and MMP-9 production in nasal fibroblasts. These results suggest that acacia honey might be useful for inhibiting nasal polyp formation.

The transition of normally quiescent glomerular MCs (mesangial cells) to a highly proliferative phenotype with characteristics of myofibroblasts is a process commonly observed in inflammatory diseases affecting the renal glomerulus, the ultimate result of which is glomerulosclerosis. Generation of proteolytically active MMP (matrix metalloproteinase)-2 by the membrane-associated membrane type 1 (MT1)-MMP is responsible for the transition of mesangial cells to the myofibroblast phenotype [Turck, Pollock, Lee, Marti and Lovett (1996) J. Biol. Chem. 271, 15074–15083]. In the present study, we show that the expression of MT1-MMP within the context of MCs is mediated by three discrete cis-acting elements: a proximal non-canonical Sp1 site that preferentially binds Sp1; an overlapping Sp1/Egr-1-binding site that preferentially binds Egr-1; and a more distal binding site for the NFAT (nuclear factor of activated T cells) that binds the NFAT c1 isoform present in MC nuclear extracts. Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. Specific binding of NFAT c1 to the MT1-MMP promoter was confirmed by chromatin immunoprecipitation studies, while MT1-MMP expression was suppressed by treatment with the calcineurin inhibitor, cyclosporin A. These studies are the first demonstration that a specific NFAT isoform enhances transcription of an MMP (MT1-MMP) that plays a major role in the proteolytic events that are a dominant feature of acute glomerular inflammation. Suppression of MT1-MMP by commonly used calcineurin inhibitors may play a role in the development of renal fibrosis following renal transplantation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix (ECM) production and abnormal lung remodeling. We have recently found that matrix metalloproteinase 19 (MMP-19)-deficient ( Mmp19−/−) mice develop an exaggerated bleomycin-induced lung fibrosis, but the mechanisms are unclear. In this study, we explored the effect of MMP-19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19−/− lung fibroblasts revealed the dysregulation of several profibrotic pathways, including ECM formation, migration, proliferation, and autophagy. Functional studies confirmed these findings. Compared with wild-type mice, Mmp19−/− lung fibroblasts showed increased α1 (I) collagen gene and collagen protein production at baseline and after transforming growth factor-β treatment and increased smooth muscle-α actin expression ( P < 0.05). Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in proliferation ( P < 0.01) and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel ( P < 0.05). These findings suggest that, in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation.

This study examined the efficacy and in vivo mechanism of action of the antifibrotic hormone, relaxin, in a mouse model of unilateral ureteric obstruction (UUO). Kidney fibrosis was assessed in recombinant human gene-2 relaxin-treated animals maintained for 3 and 9 d after UUO. Results were compared with untreated and unoperated animals (d 0). Total collagen, collagen subtypes (I, IV), TGF-β2 production, mothers against decapentaplegic homolog 2 (Smad2) phosphorylation, myofibroblast differentiation, mitosis, and apoptosis were all progressively increased by UUO (all P &lt; 0.05 vs. d 0 group at d 3 and d 9), whereas TGF-β1 production was increased and vascular endothelial growth factor expression (angiogenesis) decreased at d 9 (both P &lt; 0.05 vs. d 0). A progressive increase in matrix metalloproteinase (MMP)-2 after UUO suggested that it was reactive to the increased fibrogenesis. Conversely, MMP-9 was decreased at d 9, whereas its inhibitor tissue inhibitor of metalloproteinase-1 progressively decreased after UUO. Human gene-2 relaxin pretreatment of animals from 4 d prior to UUO ameliorated the increase in total collagen, collagen IV, Smad2 phosphorylation, and myofibroblasts at both time points (all P &lt; 0.05 vs. untreated groups) and inhibited TGF-β2 production and cell proliferation (both P &lt; 0.05 vs. untreated groups) with a trend toward normalizing vascular endothelial growth factor expression at d 9, with no effect on TGF-β1 production or apoptosis. The relaxin-mediated regulation of MMPs and tissue inhibitor of metalloproteinases in this model was not consistent with its antifibrotic properties. The beneficial effects of relaxin were lost when treatment was stopped. These findings establish that relaxin can inhibit both early and established phases of tubulointerstitial fibrosis, primarily by suppressing cell proliferation, myofibroblast differentiation, and collagen production. Not all of these effects paralleled changes to TGF-β-Smad signaling.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior
Myofibroblasts are cells that exhibit a hybrid phenotype, sharing the morphological characteristics of fibroblasts and smooth muscle cells, which is acquired during a process called differentiation. These cells then start to express -SMA, a marker that can be used for their identification. Studies suggest that myofibroblasts are related to the aggressiveness of different tumors and that TGF-1 and IFN- play a role in myofibroblast differentiation, stimulating or inhibiting this differentiation, respectively. The objective of this study was to investigate the role of myofibroblasts in epithelial odontogenic tumors, correlating the presence of these cells with the aggressiveness of the tumor. Immunohistochemistry was used to evaluate the expression of TGF-1 and IFN- in myofibroblast differentiation, as well as the expression of MMP-13, which is activated by myofibroblasts, and of EMMPRIN (extracellular matrix metalloproteinase inducer) as a precursor of this MMP. The sample consisted of 20 solid ameloblastomas, 10 unicystic ameloblastomas, 20 odontogenic keratocysts, and 20 adenomatoid odontogenic tumors. For evaluation of myofibroblasts, anti- -SMA-immunoreactive cells were quantified in connective tissue close to the epithelium. Immunoexpression of TGF-1, IFN-, MMP-13 and EMMPRIN was evaluated in the epithelial and connective tissue components, attributing scores of 0 to 4. The results showed a higher concentration of myofibroblasts in solid ameloblastomas (mean of 30.55), followed by odontogenic keratocysts (22.50), unicystic ameloblastomas (20.80), and adenomatoid odontogenic tumors (19.15) (p=0.001). No significant correlation between TGF-1 and IFN- was observed during the process of myofibroblast differentiation. There was also no correlation between the quantity of myofibroblasts and MMP-13 expression. Significant correlations were found between MMP-13 and TGF-1 (r=0.087; p=0.011), between MMP- 13 and IFN- (r=0.348; p=0.003), as well as between EMMPRIN and MMP-13 (r=0.474; p<0.001) and between EMMPRIN and IFN- (r=0.393; p=0.001). The higher quantity of myofibroblasts observed in solid ameloblastomas, odontogenic keratocysts and unicystic ameloblastomas suggests that these cells are one of the factors responsible for the more aggressive biological behavior of these tumors, although the myofibroblast population was not correlated with TGF-1, IFN-, MMP-13 or EMMPRIN. The correlation between MMP- 13 and TGF-1 suggests that the latter induces the expression of this metalloproteinase. The present results also support the well-established role of EMMPRIN as an inducer of MMP-13. Furthermore, the relationship between EMMPRIN and IFN- and between MMP-13 and IFN- suggests synergism in the antifibrotic effect of these markers
Os miofibroblastos s?o c?lulas que apresentam um fen?tipo h?brido exibindo caracter?sticas morfol?gicas de fibroblastos e de c?lulas musculares lisas, sendo a aquisi??o de tal fen?tipo denominada diferencia??o, passando ent?o a expressar a -SMA, a qual ? importante na identifica??o dessas c?lulas. Estudos t?m sugerido que os miofibroblastos apresentam rela??o com a agressividade de diversas les?es e que o seu processo de diferencia??o estaria relacionado ? express?o do TGF- 1 e do IFN- atuando, respectivamente, no est?mulo e na inibi??o dessa diferencia??o. O objetivo deste trabalho foi investigar o papel dos miofibroblastos em les?es odontog?nicas epiteliais, relacionando-os ? agressividade das les?es e analisar por meio da imuno-histoqu?mica, a express?o do TGF- 1 e IFN- no processo de diferencia??o, al?m da an?lise da MMP-13 que ? ativada por miofibroblastos e do indutor de metaloproteinases de matriz (EMMPRIN) como precursor desta MMP. A amostra foi constitu?da por 20 ameloblastomas s?lidos, 10 ameloblastomas unic?sticos, 20 ceratocistos odontog?nicos e 20 tumores odontog?nicos adenomat?ides. Para a avalia??o dos miofibroblastos, foram quantificadas as c?lulas imunorreativas ao anticorpo - SMA presentes no tecido conjuntivo, pr?ximo ao tecido epitelial. As express?es de TGF- 1, IFN- , MMP-13 e EMMPRIN, foram avaliadas no componente epitelial e no conjuntivo, estabelecendo-se o percentual de imunorreatividade e atribuindo-se escores de 0 a 4. A an?lise dos miofibroblastos evidenciou maior concentra??o nos ameloblastomas s?lidos (m?dia de 30,55), seguido pelos ceratocistos odontog?nicos (22,50), ameloblastomas unic?sticos (20,80) e tumores odontog?nicos adenomat?ides (19,15) com valor de p= 0,001. N?o foi encontrada correla??o significativa entre TGF- 1 e IFN- no processo de diferencia??o dos miofibroblastos, bem como na rela??o entre a quantidade de miofibroblastos e a express?o da MMP-13. Constatou-se, correla??o estat?stica entre MMP-13 e TGF- 1 (r= 0,087; p= 0,011) al?m de significante correla??o entre MMP-13 e IFN- (r=0,348; p=0,003). Entre EMMPRIN e MMP-13 verificou-se signific?ncia (r= 0,474; p<0,001) assim como entre EMMPRIN e IFN- (r=0,393; p=0,001). A maior quantidade de miofibroblastos evidenciada nos ameloblastomas s?lidos, ceratocistos odontog?nicos e ameloblastomas unic?sticos sugere que estas c?lulas podem ser um dos fatores respons?veis para um comportamento biol?gico mais agressivo destas les?es, embora a popula??o de miofibroblastos n?o tenha apresentado correla??o com TGF- - 1, IFN- ,MMP-13 e EMMPRIN. Quanto a correla??o evidenciada entre MMP-13 e TGF- 1, isto pode sugerir um papel indutor do TGF- 1 para a express?o da MMP-13, assim como os resultados deste estudo refor?am a rela??o bem estabelecida do EMMPRIN como indutor da MMP-13. Constatou-se tamb?m rela??o entre EMMPRIN e IFN- assim como entre MMP-13 e IFN- sugerindo, dessa forma, um sinergismo na a??o anti-fibr?tica desses marcadores

BACKGROUND AND AIMS: Congenital Hepatic Fibrosis (CHF) is caused by mutations in PKHD1, a gene encoding for fibrocystin, a protein of unknown function, expressed in cholangiocyte cilia and centromers. In CHF, biliary dysgenesis is accompanied by severe progressive portal fibrosis and portal hypertension. The mechanisms responsible for portal fibrosis in CHF are unclear. The αvβ6 integrin mediates local activation of TGFβ1 and is expressed by reactive cholangiocytes during cholestasis. To understand the mechanisms of fibrosis in CHF we studied the expression of αvβ6 integrin and its regulation in Pkhd1del4/del4 mice. METHODS: In Pkhd1del4/del4 mice we studied, at different ages (1-12 months): a) portal fibrosis (Sirius Red) and portal hypertension (spleen weight/body weight); b) αvβ6 mRNA and protein expression (RT-PCR, IHC); c) α-SMA and TGFβ1 mRNA expression (RT-PCR); d) portal inflammatory infiltrate (IHC for CD45 and FACS analysis of whole liver infiltrate); f) cytokines secretion from cultured monolayers of primary cholangiocytes (Luminex assay); g) cytokine effects on monocyte/macrophage proliferation (MTS assay) and migration (Boyden chamber); h) TGFβ1 and TNFα effects on β6 integrin mRNA expression by cultured cholangiocytes before and after inhibition of the TGFβ receptor type II (TGFβRII); i) TGFβ1 effects on collagen type I (COLL1) mRNA expression by cultured cholangiocytes. RESULTS: Pkhd1del4/del4 mice showed a progressive increase in αvβ6 integrin expression on biliary cyst epithelia. Expression of αvβ6 correlated with portal fibrosis (r=0.94, p<0.02) and with enrichment of a CD45+ve cell infiltrate in the portal space (r=0.97, p<0.01). Gene expression of TGFβ1 showed a similar age-dependent increase. FACS analysis showed that 50-75% of the CD45+ve cells were macrophages (CD45/CD11b/F4/80+ve). Cultured polarized Pkhd1del4/del4 cholangiocytes secreted from the basolateral side significantly increased amounts of CXCL1 and CXCL10 (p<0.05). Both cytokines were able to stimulate macrophage migration (p<0.05). Basal expression of β6 mRNA by cultured Pkhd1del4/del4 cholangiocytes (0.015±0.002 2^-dCt) was potently stimulated by the macrophage-derived cytokines TGFβ1 (0.017±0.002 2^-dCt, p<0.05) and TNFα (0.018±0.003 2^-dCt, p<0.05). Inhibition of TGFβRII completely blunted TGFβ1 (0.014±0.003 2^-dCt, p<0.05) but not TNFα effects (0.017±0.001 2^-dCt, p=ns) on β6 mRNA. COLL1 mRNA expression by cultured Pkhd1del4/del4 cholangiocytes (0.0009±0.0003 2^-dCt) was further and significantly increased after TGFβ1 stimulation (0.002±0.0005 2^-dCt, p<0.05). CONCLUSIONS: Pkhd1del4/del4 cholangiocytes possess increased basolateral secretory functions of chemokines (CXCL1, CXCL10) able to orchestrate macrophage homing to the peribiliary microenvironment. In turn, by releasing TGFβ1 and TNFα, macrophages up-regulate αvβ6 integrin in Pkhd1del4/del4 cholangiocytes. αvβ6 integrin activates latent TGFβ1, further increasing the fibrogenic properties of cholangiocytes.

Cardiac fibrosis results from excessive formation of the extracellular matrix by activated cardiac myofibroblasts. Ski, an endogenous repressor of the profibrotic factor transforming growth factor-β1, has been shown to attenuate the myofibroblast phenotype. We demonstrate that Ski regulates rat cardiac myofibroblast’s capacity for ECM remodeling, further solidifying its putative role as an endogenous anti-fibrotic TGF-β1 repressor. We show that Ski overexpression alters matrix metalloproteinase-2 and 9 expression and activity via immunoblotting and zymography. We also observe an attenuation of paxillin, a focal adhesion associated protein, and FAK (Tyr 397) expression by immunoblotting. Additionally, myofibroblast motility is reduced by Ski overexpression via transwell migration and scratch assay. We suggest that Ski may exert multiple effects on adverse ECM remodeling by altering the expression and function of the ECM proteases. The effects of Ski on cell motility also represent a putative mechanism for modulation of myofibroblast function in progression of cardiac fibrosis.
February 2016

AbstractShock Wave Therapy (SWT) meets all the requirements for the ideal non-invasive scar treatment. It is safe, well tolerated by patients, cost-effective, easy to apply, has low complication rates, and can be used in an outpatient setting. The overall effect of SWT is an improvement of tissue homeostasis, accompanied by an improvement of the tissue self-healing abilities, and it seems to focus on inducing tissue regeneration and matrix remodeling in vivo by means of mechanotransduction.SWT has a beneficial effect on wound healing and is characterized by an upregulation of the angio-active factors as nitric oxide (NO) and vascular endothelial growth factor (VEGF) leading to induced angiogenesis. A downregulation of alpha-SMA expression, myofibroblast phenotype, TGF-β1 expression, fibronectin, and collagen type I are measured after SWT on scars, leading to improvement of several relevant scar parameters like height, pliability, vascularity, and pigmentation, and thus ameliorating function.For a full treatment outline, the energy flux density (EFD), the number of pulses, the pulse frequency, and the number and interval of treatments are the most relevant parameters. The EFD for soft tissue indications is typically in the range of 0.08–0.25 mJ/mm2, while scars and fibrosis are treated with an EFD ranging between 0.15 and 0.33 mJ/mm2. These settings seem to be ideal to induce the optimal cell responses for each indication.All the presented findings are fundamental knowledge for further investigation of SWT to reduce the fibrous component in regenerating and remodeling tissues. However, the full potential of SWT in wound healing and scar treatment needs further unraveling.

Background: Malignancy related ascites encompasses multiple etiologies which include peritoneal carcinomatosis, hepatic synthetic dysfunction due to parenchymal involvement by the tumour, transcoeloemic metastasis and chylous ascites due to lymphatic obstruction. Primary Cancer type, liver metastasis and serum albumin have been listed as independent prognostic markers in malignant ascites. Spontaneous Bacterial Peritonitis is usually seen as a complication of decompensated chronic liver disease due to translocation of bacteria or haematogenous dissemination from a distant focus of infection. The combination of a positive peritoneal fluid culture and an ascitic fluid neutrophil count >250 cells/mm3 and no evidence of intra-abdominal source of infection; or 2) culture negative neutrocytic ascites: the combination of negative peritoneal fluid bacterial culture and neutrophil count >500 cells/mm3, without antibiotics within 7 days with no obvious source of infection are used to define spontaneous bacterialperitonitis. Ciprofloxacin prophylaxis has been proposed as a prophylaxis to reduce the incidence and prevent the recurrence of spontaneous bacterial peritonitis. Materials and Methods: A web search of indexed literature was carried out articles containing information on spontaneous bacterial peritonitis in the setting of malignancy or malignancy related ascites or malignant ascites. Articles that carried relevant information about etiopathogenesis, management and translational research in the context of malignant ascites were also included. Results: A total of 32 articles were analysed and about half of them included in the discussion to answer the research question. Discussion: Inflammatory cytokines released by tumor and immune cells compromise the mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach leading to formation of spheroids which imparts resistance to anoikis, apoptosis and chemotherapeutics leading to efficient feed forward progressive cycle of seeding and growth of peritoneal metastasis. Intraperitoneal metastasis can cause peritoneal dysfunction, adhesions and malignant ascites. Epithelial mesenchymal transistion and myofibroblastic transformation occur in the mesothelial cells in response to pathological stimuli. Vascular endothelial growth factor is an important mitogen for endothelial cells and plays an important role in increasing capillary vascular permeability. In preclinical studies systemic administration of VEGF Trap which acts as a decoy receptor for VEGF has shown to decrease the formation of ascites fluid and prevent tumour dissemination. Epithelial ovarian cancer cells have developed various mechanisms to evade immune surveillance like development of surface microvesicles which contain CD 95 ligand leading to apoptosis of immune cells. Higher levels of osteoproteogerin, IL 10 and leptin in the ascitic fluid have been associated with a poor prognosis in malignant ascites. Tethered bowel sign and presence of fluid in the omental bursa on CT have been shown to distinguish between malignant ascites and Cirrhotic ascites with accuracy. Immunological approaches to management of malignant ascites include use of intraperitoneal triamcinolone, interferon, long acting synthetic corticosteroids and the trifoliate antibody catumaxomab. VEGF Inhihibitors like octreotide and long acting depot preparations of lanreotide have also been shown to be feasible therapeutic options. Anti androgenic agents and PARP inhibitors have also been proposed as management options. Spontaneous bacterial peritonitis in the setting of malignancy in the absence of hepatic dysfunction has been reported to have a poorer prognosis than SBP in the setting of decompensated liver disease. Monomicrobial and polymicrobial bacterascites have been proposed in the absence of an elevated neutrophil ascitic fluid count that does not meet the diagnostic criteria. Extensive liver metastasis where the diseased liver can be expected to behave like a cirrhotic liver and gastrointestinal bleeding (on the basis of an isolated case report) have been considered as risk factors for the development of SBP in malignant ascites. In a case series of 8 patients with malignancy related ascites Patients with total ascitic fluid concentration of less than 1 gm per litre were found to be at risk for Spontaneous bacterial peritonitis and warrant flouroquinolone prophylaxis. Conclusion: Spontaneous Bacterial Peritonitis complicating malignant ascites is questionable entity. Good quality Audits and Randomised control trials are warranted to in this domain to enable the definition of incidence, antecedent complications, management and prophylaxis to ensure applicability of translational research to the clinical domain.