Effects of p38 MAPK inhibitors on fibroblast differentiation in the zone of postoperative scar formation

Цель исследования: оценить влияние блокатора р38 МАРК SB203580 на дифференцировку фибробластов в зоне формирования послеоперационного рубца. Материалы и методы: На модели линейной кожно-мышечной раны у крыс линии Вистар оценено влияние локального введения блокатора р38 МАРК SB203580 в составе лекарственной пленки на дифференцировку фибробластов (n = 30) по сравнению с заживлением раны без введения активного вещества (n = 30). Проводили оценку количества коллагена в области раны, периоперационной зоне и интактной дерме, а также иммуноморфологическое окрашивание на CD34, CD45, ММР9 и актин в сроки от 2 часов до 30 суток. Результаты: Установлено, что применение блокатора р38 SB203580 приводило к значительному снижению интенсивности коллагенообразования в зоне формирующегося рубца. Так, у животных контрольной группы относительная площадь, занятая волокнами коллагена в зоне послеоперационной раны, закономерно возрастала в сроки от 3 до 30 суток, достигая максимальных значений к концу наблюдения - 73,54% [66,87; 78,01]. При введении SB203580 в течение всего срока наблюдения отмечалось достоверное снижение коллагенообразования в сравнении с группой контроля, к 30 суткам показатель составил 43,60% [41,05; 60,15] (р = 0.002). Введение SB203580 снижало привлечение прогениторных клеток фибробластического ряда в зону формирования послеоперационного рубца, повышало фиброкластическую активность. Aim. To assess effects of a p38 MAPK inhibitor, SB203580, on fibroblast differentiation in the zone of postoperative scar formation. Materials and methods. The effect of locally injected p38 MAPK inhibitor, SB203580, on fibroblast differentiation (n = 30) was compared with wound healing without an active substance injection (n = 30) on a model of linear musculocutaneous wound in Wistar rats weighing 220-250 g. We measured the amount of collagen in the wound zone, perioperative zone, and intact derma and conducted immunomorphological staining for CD34, CD45, MMP9, and actin at timepoints of 2 hours to 30 days. Results. The p38 inhibitor, SB203580, induced a significant decrease in collagenation intensity in the zone of forming scar. In Wistar rats of the control group, the percent area of collagen fibers in the zone of postoperative wound was increasing between days 3 and 30 and reached a maximum of 73.54 % [66.87; 78.01] by the end of observation period. The SB203580 injection significantly decreased collagenation over the entire period of observation compared with the control group (43.60 % [41.05; 60.15] by day 30, р = 0.002). The SB203580 injection decreased the engagement of fibroblastic progenitors in the zone of postoperative scar formation and increased the fibroclast activity.

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507. TGFβ REGULATES ENDOMETRIOSIS-LIKE LESION DEVELOPMENT IN MICE INDEPENDENTLY OF THE RUNX-2/OPN PATHWAY

Reproduction Fertility and Development ◽

10.1071/srb09abs507 ◽

2009 ◽

Vol 21 (9) ◽

pp. 107

Author(s):

M. Z. Johan ◽

W. V. Ingman ◽

S. A. Robertson ◽

M. Hull

Keyword(s):

P38 Mapk ◽

Nude Mouse ◽

Immunohistochemical Analysis ◽

Endometriotic Lesion ◽

Lesion Development ◽

Nude Mouse Model ◽

P38 Mapk Inhibitors ◽

Mapk Inhibitors ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

TGFβ is likely to significantly influence endometriotic lesion development, as TGFβ KO/SCID mice with no host-derived TGFβ activity have smaller human ectopic endometrial lesions than control mice. TGFβ potentially acts via RUNX2, a transcription factor that directly upregulates OPN transcription in osteoblasts, as we have identified RUNX-2 and OPN gene expression at high levels in nude mouse endometriosis-like lesions, in human endometrial stomal cell cultures and in the stroma of endometriotic tissues. We hypothesised that inhibition of RUNX-2 would suppress OPN production and result in reduction of endometriotic lesion formation and size. As P38/MAPK inhibitors suppress TGF-β mediated RUNX-2 transcription, we utilised the nude mouse model to test whether the P38/MAPK inhibitor FR167653 would suppress OPN production in endometriotic tissues resulting in smaller lesions.FR167653 (30 mg/kg twice a day) or placebo was administered for either 10 or 14 days to nude mice (16 in each group) implanted with human endometrial tissue xenografts from 4 different women. The size and weight of the lesions were measured and immunohistochemical analysis of OPN, αSMA (myofibroblasts) and F4/80 (macrophages) was carried out. There was no difference in size or weight of the lesions, and there was no overt difference in any of the staining parameters explored. The inhibition of p38/MAPK did not alter the size of the nude mouse lesions nor OPN staining within these lesions despite being administered at a maximal therapeutic dose. This suggests that TGFβ regulation of endometriotic lesion development is mediated by an alternate molecular pathway.

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Effect of the p38 MAPK Inhibitor on the Expression of Metalloproteinases and Their Inhibitors during the Formation of Abdominal Adhesions

International Journal of Biomedicine ◽

10.21103/article11(4)_oa9 ◽

2021 ◽

Vol 11 (4) ◽

pp. 446-450

Author(s):

Irina Shurygina ◽

Lyubov Rodionova ◽

Natalia Ayushinova ◽

Elena Chepurnykh ◽

Irina Trukhan ◽

...

Keyword(s):

P38 Mapk ◽

Abdominal Cavity ◽

Adhesion Formation ◽

Intraperitoneal Administration ◽

Mitogen Activated Protein Kinase ◽

Control Group ◽

Genes Encoding ◽

Male Wistar Rats ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

Background: The aim of this study was to assess the effect of blockade of the p38 mitogen-activated protein kinase (MAPK) on the expression of genes encoding metalloproteinases (MMPs) during the formation of adhesions in the abdominal cavity. Methods and Results: The experiments were carried out on male Wistar rats (n=75). The studies were carried out in two groups: Group 1 (control, n=35) – modelling the adhesive process; Group 2 (experimental, n=35) – modelling the adhesive process with intraperitoneal administration of Seroguard®—a prolonged form of the p38 MAPK inhibitor. The expression of the MMP1a, MMP2, MMP7, MMP9, and TIMP genes was assessed using real-time PCR. In the control group, overexpression of the MMP1a and MMP7 genes began from 6 hours after modeling the adhesive process, MMP9 – from Day 1, MMP2 – from Day 7 and persisted until the end of observation. With local blockade of p38 MAPK, the level of overexpression of genes encoding MMPs in the early stages was higher than in the control group (MMP1a – by Day 1; MMP7 – by 6 hours and Day 1, MMP9 – by 12 hours). From Day 3 to Day 14, the MMP1a and MMP7 expression in the experimental group was significantly lower than in the control group. Conclusion: The performed study demonstrated the involvement of different types of MMPs—collagenases (MMP1a), gelatinases (MMP2 and 9), matrilysins (MMP7)—in the rearrangement of the extracellular matrix during the process of adhesion formation in the abdominal cavity.

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Peripheral Injection of SB203580 Inhibits the Inflammatory-Dependent Synthesis of Proinflammatory Cytokines in the Hypothalamus

BioMed Research International ◽

10.1155/2014/475152 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 19

Author(s):

Andrzej P. Herman ◽

Agata Krawczyńska ◽

Joanna Bochenek ◽

Hanna Antushevich ◽

Anna Herman ◽

...

Keyword(s):

Gene Expression ◽

P38 Mapk ◽

Proinflammatory Cytokines ◽

Inflammatory Diseases ◽

Competitive Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitors ◽

Mapk Inhibitors ◽

P38 Mapk Inhibitor

The study was designed to determine the effects of peripheral injection of SB203580 on the synthesis of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF)αin the hypothalamus of ewes during prolonged inflammation. Inflammation was induced by the administration of lipopolysaccharide (LPS) (400 ng/kg) over 7 days. SB203580 is a selective ATP-competitive inhibitor of the p38 mitogen-activated protein kinase (MAPK), which is involved in the regulation of proinflammatory cytokines IL-1β, IL-6 and TNFαsynthesis. Intravenous injection of SB203580 successfully inhibited (P<0.01) synthesis of IL-1βand reduced (P<0.01) the production of IL-6 in the hypothalamus. The p38 MAPK inhibitor decreased (P<0.01) gene expression of TNFαbut its effect was not observed at the level of TNFαprotein synthesis. SB203580 also reduced (P<0.01) LPS-stimulated IL-1 receptor type 1 gene expression. The conclusion that inhibition of p38 MAPK blocks LPS-induced proinflammatory cytokine synthesis seems to initiate new perspectives in the treatment of chronic inflammatory diseases also within the central nervous system. However, potential proinflammatory effects of SB203580 treatment suggest that all therapies using p38 MAPK inhibitors should be introduced very carefully with analysis of all expected and unexpected consequences of treatment.

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