Role of Fibroblasts and Myofibroblasts on the Pathogenesis and Treatment of Pelvic Organ Prolapse

Pelvic organ prolapse (POP) is a multifactorial connective tissue disorder caused by damage to the supportive structures of the pelvic floor, leading to the descent of pelvic organs in the vagina. In women with POP, fibroblast function is disturbed or altered, which causes impaired collagen metabolism that affects the mechanical properties of the tissue. Ideal surgical repair, either native tissue repair or POP surgery using an implant, aims to create a functional pelvic floor that is load-bearing, activating fibroblasts to regulate collagen metabolism without creating fibrotic tissue. Fibroblast function plays a crucial role in the pathophysiology of POP by directly affecting the connective tissue quality. On the other hand, fibroblasts determine the success of the POP treatment, as the fibroblast-to-(myo)fibroblast transition is the key event during wound healing and tissue repair. In this review, we aim to resolve the question of “cause and result” for the fibroblasts in the development and treatment of POP. This review may contribute to preventing the development and progress of anatomical abnormalities involved in POP and to optimizing surgical outcomes.

The Stiffness of Cardiac Fibroblast Substrates Exerts a Regulatory Influence on Collagen Metabolism via α2β1 Integrin, FAK and Src Kinases

Information about mechanical strain in the extracellular space is conducted along collagen fibers connected with integrins and then transmitted within cells. An aim of the study is to verify the hypothesis that the stiffness of cardiac human fibroblast substrates exerts a regulatory effect on collagen metabolism via integrin α2β1 and downstream signaling. The experiments were performed on human cardiac fibroblasts cultured on stiff or soft polyacrylamide gels. Extracellular and intracellular collagen content, metalloproteinase-1 (MMP-1), metalloproteinase-9 (MMP-9) and expression of the α1 chain of the procollagen type I gene (Col1A1) were elevated in cultures settled on soft substrate. The substrate stiffness did not modify tissue inhibitors of matrix metalloproteinase capacity (TIMPs 1–4). Integrin α2β1 inhibition (TC-I 15) or α2 subunit silencing resulted in augmentation of collagen content within the culture. Expression of Col1A1 and Col3A1 genes was increased in TC-I 15-treated fibroblasts. Total and phosphorylated levels of both FAK and Src kinases were elevated in fibroblasts cultured on stiff substrate. Inhibition of FAK (FAK kinase inhibitor 14) or Src kinase (AZM 47527) increased collagen content within the culture. The substrate stiffness exerted a regulatory influence on collagen metabolism via integrin α2β1 and its downstream signaling (FAK and Src kinases) in cardiac fibroblasts.

Monitoring urinary collagen metabolite changes following collagen peptide ingestion and physical activity using ELISA with anti active collagen oligopeptide antibody

Active collagen oligopeptides (ACOP) are bioactive collagen-derived peptides detected by a recently-established ELISA. To facilitate studies of the function and metabolism of these products, this study aims to determine which of these peptides is recognized by a novel anti-ACOP antibody used in this ELISA. We then investigate the effect of collagen peptide (CP) ingestion and exercise on urinary ACOP concentrations in a cohort of university student athletes using colorimetric, LC–MS/MS, and ELISA. We observed that the antibody showed strong cross-reactivity to Pro-Hyp and Gly-Pro-Hyp and weak cross-reactivity to commercial CP. CP ingestion increased the urinary level of ACOP over time, which correlated highly with urinary levels of peptide forms of Hyp and Pro-Hyp. Physical activity significantly decreased the urinary ACOP level. This study demonstrates changes in urinary ACOP following oral CP intake and physical activity using ELISA with the novel anti-ACOP antibody. Thus, ACOP may be useful as a new biomarker for collagen metabolism.

ASSESSMENT OFTHE SEVERITY OF ACUTE OBSTRUCTIVE BRONCHITIS AND BRONCHIOLITIS IN EARLY CHILDREN DEPENDING ON THE LEVEL OF OXIPROLIN IN THE BLOOD

The article presents data on the state of collagen metabolism in terms of oxyproline in the blood, its clinical significance for assessing the severity and outcome of the disease, the criterion for the effectiveness of therapy in children of early age withacute obstructive bronchitis and bronchiolitis. The author recommends to determine the level of free and protein-bound oxyproline in blood plasma, an increase in which reflects the degree of destruction in the bronchopulmonary apparatus. The inclusion of immunomodulin into the basic treatment contributes to an increase in the effectiveness of therapy, a reduction of treatment duration.Keywords: oxyproline, bronchitis and bronchiolitis, immunomodulin, treatment, children

Monitoring Urinary Collagen Metabolite Changes Following Collagen Peptide Ingestion and Physical Activity Using ELISA With Anti–Active-Collagen-Oligopeptide Antibody

Active collagen oligopeptides are bioactive collagen-derived peptides detected by a recently-established ELISA. To facilitate studies of the function and metabolism of these products, this study aims to determine which of these peptides is recognized by a novel anti-ACOP antibody used in this ELISA. We then investigate the effect of collagen peptide (CP) ingestion and exercise on urinary ACOP concentrations in a cohort of university student athletes using colorimetric, LC-MS/MS, and ELISA. We observed that the antibody showed strong cross-reactivity to Pro-Hyp and Gly-Pro-Hyp and weak cross-reactivity to commercial CP. CP ingestion increased the urinary level of ACOP over time, which correlated highly with urinary levels of peptide forms of Hyp and Pro-Hyp. Physical activity significantly decreased the urinary ACOP level. This study demonstrates changes in urinary ACOP following oral CP intake and physical activity using ELISA with the novel anti-ACOP antibody. Thus, ACOP may be useful as a new biomarker for collagen metabolism.

Menopause, Ultraviolet Exposure, and Low Water Intake Potentially Interact with the Genetic Variants Related to Collagen Metabolism Involved in Skin Wrinkle Risk in Middle-Aged Women

Genetic and environmental factors influence wrinkle development. We evaluated the polygenetic risk score (PRS) by pooling the selected single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) for wrinkles and the interaction of PRS with lifestyle factors in middle-aged women. Under the supervision of a dermatologist, the skin status of 128 women aged over 40 years old was evaluated with Mark-Vu, a skin diagnosis system. PRS was generated from the selected SNPs for wrinkle risk from the genome-wide association study. Lifestyle interactions with PRS were also evaluated for wrinkle risk. Participants in the wrinkled group were more likely to be post-menopausal, eat less fruit, take fewer vitamin supplements, exercise less, and be more tired after awakening in the morning than those in the less-wrinkled group. The PRS included EGFR_rs1861003, MMP16_rs6469206, and COL17A1_rs805698. Subjects with high PRS had a wrinkle risk 15.39-fold higher than those with low PRS after adjusting for covariates, and they had a 10.64-fold higher risk of a large skin pore size. Menopause, UV exposure, and water intake interacted with PRS for wrinkle risk: the participants with high PRS had a much higher incidence of wrinkle risk than those with low PRS, only among post-menopausal women and those with UV exposure. Only with low water intake did the participants with medium PRS have increased wrinkle risk. In conclusion, women aged >40 years with high PRS-related collagen metabolism may possibly avoid wrinkle risk by avoiding UV exposure by applying sunscreen, maintaining sufficient water intake, and managing estrogen deficiency.

EFFECT OF PHARMACOTHERAPY ON COLLAGEN METABOLISM IN PATIENTS WITH HEART FAILURE WITH MIDDLE RANGE EJECTION FRACTION OF SENILE AGE

Особый интерес представляет изучение механизмов развития ХСН, особенно c промежуточной ФВ (ХСНпрФВ), у больных старческого возраста. В условиях ХСН многократно возрастает значимость развития фиброза миокарда, приводящего к необратимой дисфункции, что способствует дальнейшему прогрессированию ХСН. Фибрилляция предсердий является дополнительным фактором, способствующим систолической дисфункции ЛЖ. Цель исследования -изучение влияния β-блокаторов на изменения маркеров фиброза у больных старческого возраста с ХСНпрФВ, в том числе и с фибрилляцией предсердий. Обследованы 104 больных ХСНпрФВ ишемического генеза II ФК по классификации NYHA, средний возраст - 78,4±3,2 года. Через 12 мес нами выявлено достоверное снижение уровня матриксной металлопротеиназы 1-го типа, 9-го типа (ММП-1, ММП9), тканевого ингибитора ММП-1 (ТИМП-1), а также соотношения ММП-1/ТИМП-1, ММП-9/ТИМП-1 у больных старческого возраста, имеющих ХСНпрФВ ишемического генеза, в том числе и с фибрилляцией предсердий (ММП-1, ММП-9, ТИМП-1, ММП-9/ТИМП-1), принимавших в качестве β-блокатора небиволол. У больных, принимавших бисопролол, достоверных изменений изучаемых показателей не выявлено (кроме ММП-9). Изменения метаболизма коллагена обусловливают восстановление функции миокарда после терапии β-блокатором небивололом у пациентов с ХСНпрФВ, в том числе и при фибрилляции предсердий. Сывороточные маркеры оборота коллагена могут служить неинвазивным методом документирования и мониторинга как степени, так и механизмов фиброза миокарда у больных ХСНпрФВ ишемического генеза, в том числе и на фоне фибрилляции предсердий. Of particular interest is the study of the mechanisms of development of chronic heart failure, especially with middle range ejection fraction (HFmrEF). In conditions of HF, the significance of the development of myocardial fibrosis increases many times, leading to irreversible dysfunction, which contributes to the further progression of HF. Atrial fibrillation is an additional factor contributing to systolic dysfunction of the left ventricle. The purpose of this study was to study the effect of beta-blockers on changes in fibrosis markers in senile patients with HF, including those with AF. 104 patients with HF, coronary disease of functional class II were examined according to the classification of NYHA, the average age was 78,4±3,2 years. After 12 months, we found a significant decrease in the level of matrix metalloproteinase-type 1, -type 9 (MMP-1, MMP-9), tissue inhibitor MMP-1 (TIMP-1), as well as the ratio of MMP-1/TIMP-1, MMP-9/TIMP-1 in senile patients with HF, including those with atrial fibrillation who took nebivolol as a beta-blocker. While in patients who took bisoprolol, no significant changes in the studied parameters were detected (except for MMP-9). Changes in collagen metabolism cause the restoration of myocardial function after therapy with the beta-blocker nebivolol in patients with chronic heart failure with an middle range ejection fraction, including atrial fibrillation. Serum markers of collagen turnover can serve as a noninvasive method for documenting and monitoring both the degree and mechanisms of myocardial fibrosis in patients with HF, coronary disease, including in the presence of AF.

Status of the collagen metabolism and intracardiac hemodynamics in patients with mitral valve prolapse and diabetes mellitus type 1

Summary. Mitral valve prolapse is a significant cardiovascular risk factor in young adults. Its combination with type 1 diabetes mellitus can influence the nature and development of the disease. Objective – a comparative analysis of free and peptide-bound oxyproline levels and basic echocardiographic parameters (ECP) in patients with mitral valve prolapse, type 1 diabetes and their combination. Materials and methods – 93 people aged 19–33 years were examined, including 24 people with mitral valve prolapse without concomitant pathology; 33 patients with mitral valve prolapse and type 1 diabetes; 36 patients with type 1 diabetes without mitral valve prolapse. Results. The level of free and peptide-bound oxyproline in blood serum and their ratio were assessed as a marker of collagen metabolism. The levels of free oxyproline were significantly higher only for the group of MVP patients with type 1 diabetes (p < 0.05) compared to the control group. Severity of destructive processes was demonstrated by a high level of peptide-bound oxyproline, both in combined pathology compared with control group, and compared with groups of patients with monomorbid diabetes and MVP (p < 0.05). In patients with mitral valve prolapse and type 1 diabetes for more than 10 years in anamnesis were found significant differences in the echocardiography parameters (ventricular septum thickness, posterior wall of the left ventricle thickness) compared with the subgroup of patients with less than 10 years of type 1 diabetes in anamnesis and the group with isolated mitral valve prolapse. Conclusions. The data obtained indicate an aggravation in collagen metabolism disorders in patients with mitral valve prolapse depending on the duration of type 1 diabetes, and demonstrate the effect of carbohydrate metabolism disorders on the risk of developing connective tissue degradation of the heart valve apparatus.

Disorders of Proteoglycan and Collagen Metabolism in the Kidneys in Diabetes Mellitus: Clinical and Pathogenetic Mechanisms and Laboratory Markers

The article considers the issue of disorders of connective tissue metabolism in diabetes mellitus. Glycosylation of structural components of connective tissue and glucose toxicity have been found to determine the pathogenesis of late complications of diabetes mellitus. The most common concept of the pathogenesis of diabetes is metabolic, according to which all variants of diabetes mellitus, including blood vessels, their basement membrane, are associated with primary disorders of lipid, glycoprotein, protein and carbohydrate metabolism due to complete or partial insufficiency. It has been found that the formation of interstitial fibrosis in the kidneys of patients with diabetes begins in the preclinical stages of diabetic nephropathy. The leading cause of interstitial fibrogenesis is hyperglycemia; exacerbate proteinuria fibrosis, activation of the renin-angiotensin system, chronic inflammation and the formation of myofibroblasts in the interstitium. According to the results of the study of aspects of early diagnosis of kidney damage in type 1 diabetes mellitus, it was found that the development of diabetic nephrosclerosis is characterized by qualitative and quantitative changes in collagen composition in the glomeruli and interstitium, rebalance between collagen synthesis and breakdown, glycosaminoglycans, increased synthesis of fibrogenic growth factors and oxidative modification of proteins. The formation of diabetic nephropathy in patients with diabetes is also characterized by the accumulation of collagen types IV and VI, the appearance of interstitial collagen types III and I in the glomeruli, as well as the accumulation of collagen of all types in tubulointerstitium. Quantitative and qualitative characteristics of sulfated glycosaminoglycans of urine in human diabetes indicated different degrees of development of diabetic nephropathy. Glycosaminoglycans hyperexcretion was observed in patients with diabetes mellitus without proteinuria. In patients with microalbuminuria, glycosaminoglycans hyperexcretion was even more pronounced. It was also found that in diabetes, the total excretion of sulfated glycosaminoglycans in the urine doubles. Conclusion. Thus, in diabetes mellitus, an important pathogenetic link in the violation of the morpho-functional state of the kidneys is the degradation of collagen and proteoglycans of the basement membranes of the glomeruli, as well as interstitial fibrosis. This is reflected in changes in urinary glycosaminoglycans excretion, in particular heparansulfate and chondroitin sulfate, which may serve as a marker of proteoglycan metabolism disorders in the kidneys. Patients with diabetes also have an increase in the urine of hydroxyproline, which indicates an increase in the intensity of collagen metabolism in patients