The role of tissue inhibitor of metalloproteinases in the aetiology of inguinal and incisional hernias.

Inguinal and incisional hernias are the two most common types of hernias caused by abdominal wall weakness and defects in connective tissue. The structure of the extracellular matrix, mainly collagen and metalloproteinases (MMPs), and their regulators have been studied extensively and found to play a significant role in the pathophysiology of hernias. One of the regulators of MMPs, tissue inhibitor metalloproteinases (TIMPs), bind to MMPs and inhibit its activity significantly shifting the balance towards collagen synthesis rather than degradation. Due to their importance in collagen metabolism, their metabolism might be significant in the aetiology of hernias. Our study used immunohistochemical techniques to investigate the possible effects of TIMP 1 and 2 on the samples taken from the abdominal walls of patients with inguinal and incisional hernias, compared them with control patients, and reviewed the literature. In this study, samples of 90 patients (30 patients from control, inguinal hernia, and incisional hernia groups) were taken and analysed. These samples were stained with TIMP-1 Ab-2 and TIMP2 Ab-5 (Clone 3A4) antibodies and evaluated under ×100 magnification. The degree of staining was classified as (a): No staining (0), (b): Staining less than 10% (I), (c): Staining between 10% and 50% (II), (d): Staining more than 50% (III). Statistical analyses were done. No significant difference was found between groups in terms of patient demographics. Smoking and family history of hernia was not found to be associated with TIMP expression. TIMP1 expression was significantly higher in the incisional and inguinal hernia group than in the control group (P < .05), while the level of TIMP2 was higher in the control group. (P < .05). TIMP1 and TIMP2 levels did not significantly differ between incisional and inguinal hernia groups. We found significantly increased TIMP-1 levels in tissue samples from patients with hernia supporting its suggested role in hernia pathophysiology. Local alterations in MMP and TIMP levels might play a role in the pathogenesis of hernias. Thus detection of TIMP in tissues can be important for clinical use after further validation studies. In the era of molecular medicine, detecting TIMP levels in hernia patients can impact clinical practice.

Biomarkers and heterogeneous fibroblast phenotype associated with incisional hernia.

Development of incisional hernia (IH) is multifactorial but inflammation and abdominal wall ECM (extracellular matrix) disorganization are key pathological events. We investigated if the differential expression of fibroblast biomarkers reflects the cellular milieu and the dysregulated ECM in IH tissues. Expression of fibroblast biomarkers, including connective tissue growth factor, alpha-smooth muscle actin (α-SMA), CD34 (cluster of differentiation 34), cadherin-11 and fibroblast specific protein 1 (FSP1), was examined by histology and immunofluorescence in the hernial-fascial ring/neck tissue (HRT) and hernia sack tissue (HST) harvested from the patients undergoing hernia surgery and compared with normal fascia (FT) and peritoneum (PT) harvested from brain-dead healthy subjects undergoing organ procurement for transplantation. The H&E staining revealed alterations in tissue architecture, fibroblast morphology, and ECM organization in the IH tissues compared to control. The biomarker for undifferentiated fibroblasts, CD34, was significantly higher in HST and decreased in HRT than the respective FT and PT controls. Also, the findings revealed an increased level of CTGF (connective tissue growth factor) with decrease in α-SMA in both HRT and HST compared to the controls. In addition, an increased level of FSP1 (fibroblast specific protein 1) and cadherin-11 in HRT with decreased level in HST were observed relative to the respective controls (FT and PT). Hence, these findings support the heterogeneity of fibroblast population at the laparotomy site that could contribute to the development of IH. Understanding the mechanisms causing the phenotype switch of these fibroblasts would open novel strategies to prevent the development of IH following laparotomy.

Selected conditions associated with an increased incidence of incisional hernia: A review of molecular biology.

BACKGROUND: Incisional hernias (IH) following a laparotomy, on average, occur in 10-20% of patients, however, little is known about its molecular basis. Thus, a better understanding of the molecular mechanisms could lead to the identification of key target(s) to intervene pre-and post-operatively. METHODS: We examined the current literature describing the molecular mechanisms of IH and overlap these factors with smoking, abdominal aortic aneurysm, obesity, diabetes mellitus, and diverticulitis. RESULTS: The expression levels of collagen I and III, matrix metalloproteinases, and tissue inhibitors of metalloproteases are abnormal in the extracellular matrix (ECM) of IH patients and ECM disorganization has an overlap with these comorbid conditions. CONCLUSION: Understanding the pathophysiology of IH development and associated risk factors will allow physicians to identify patients that may be at increased risk for IH and to possibly act preemptively to decrease the incidence of IH.

Type V Collagen is Persistently Altered After Inguinal Hernia Repair.

BACKGROUND AND AIMS: Hernia formation is associated with alterations of collagen metabolism. Collagen synthesis and degradation cause a systemic release of products, which are measurable in serum. Recently, we reported changes in type V and IV collagen metabolisms in patients with inguinal and incisional hernia. The aim of this study was to determine if the altered collagen metabolism was persistent after hernia repair. MATERIAL AND METHODS: Patients who had undergone repairs for inguinal hernia (n = 11) or for incisional hernia (n = 17) were included in this study. Patients who had undergone elective cholecystectomy served as controls (n = 10). Whole venous blood was collected 35-55 months after operation. Biomarkers for type V collagen synthesis (Pro-C5) and degradation (C5M) and those for type IV collagen synthesis (P4NP) and degradation (C4M2) were measured by a solid-phase competitive assay. RESULTS: The turnover of type V collagen (Pro-C5/C5M) was slightly higher postoperatively when compared to preoperatively in the inguinal hernia group (P = 0.034). In addition, the results revealed a postoperatively lower type V collagen turnover level in the inguinal hernia group compared to controls (P = 0.012). In the incisional hernia group, the type V collagen turnover was higher after hernia repair (P = 0.004) and the postoperative turnover level was not different from the control group (P = 0.973). CONCLUSION: Patients with an inguinal hernia demonstrated a systemic and persistent type V collagen turnover alteration. This imbalance of the collagen metabolism may be involved in the development of inguinal hernias.

Advanced glycation end products as a biomarker for incisional hernia.

BACKGROUND: Incisional hernia is one of the most frequent complications after abdominal surgery, with incidences up to 30%. A reliable biomarker for the prediction of this complication is lacking. Advanced glycosylation end products (AGEs), also known as non-enzymatic collagen crosslinks, are correlated with aging, smoking, hyperglycemia, hyperlipidemia and oxidative stress. In this study the accumulation of AGEs and the relation between AGEs and incisional hernia were investigated. MATERIALS AND METHODS: In an exploratory case-control study, 23 patients with incisional hernia after midline incision were compared with 17 patients without clinical or radiological signs of incisional hernia after midline incision, AGEs were measured using a Skin Auto Fluorescence (SAF)-reader. RESULTS: Twenty-three patients with a clinically significant incisional hernia and 17 control patients were included. The study groups had significant differences in mean BMI. There was a significant difference between mean AGEs in patients with and without incisional hernia after midline incision (3.00 ± 0.15 vs. 2.56 ± 0.11, T test p = 0.03). CONCLUSION: AGE accumulation measured in the skin indirectly with autofluorescence might be associated with incisional hernia. Prospective larger trials should confirm this finding.

Characteristics of the fibroplasia and collagen expression in the abdominal wall after implant of the polypropylene mesh and polypropylene/polyglecaprone mesh in rats.

PURPOSE: To compare fibroplasia and the resistance of the abdominal wall when polypropylene meshes and polypropylene/poliglecaprone are used. METHODS: Seventy-seven male Wistar rats were divided into three groups: Control Group (for resistance); Group E (polypropylene mesh); and Group U (polypropylene/poliglecaprone mesh). The animals in Groups E and U had a standard muscular and aponeurotic defect, with integral peritoneum, and correction with the mesh. Measurements were taken 4, 7, 14, 28 and 56 days after surgery. The resistance, and collagen density were studied. RESULTS: Resistance on the 56th day was similar in both meshes. The gain in resistance described an ascending curve for the polypropylene mesh and was irregular in the case of the polypropylene/poliglecaprone. Fibroplasia showed a gain in type I and type III collagen in both groups (p<0.001). Collagen III stabilized in the 14th day and collagen I continued to ascend. CONCLUSIONS: The gain in resistance of the polypropylene mesh is regular and ascending, whereas the polypropylene/poliglecaprone is not regular. The final resistance of both meshes is similar; the collagen density increases over time, and show the same inflammatory potential.

Characteristics of the fibroplasia and collagen expression in the abdominal wall after implant of the polypropylene mesh and polypropylene/polyglecaprone mesh in rats

ABSTRACT PURPOSE: To compare fibroplasia and the resistance of the abdominal wall when polypropylene meshes and polypropylene/poliglecaprone are used. METHODS: Seventy-seven male Wistar rats were divided into three groups: Control Group (for resistance); Group E (polypropylene mesh); and Group U (polypropylene/poliglecaprone mesh). The animals in Groups E and U had a standard muscular and aponeurotic defect, with integral peritoneum, and correction with the mesh. Measurements were taken 4, 7, 14, 28 and 56 days after surgery. The resistance, and collagen density were studied. RESULTS: Resistance on the 56th day was similar in both meshes. The gain in resistance described an ascending curve for the polypropylene mesh and was irregular in the case of the polypropylene/poliglecaprone. Fibroplasia showed a gain in type I and type III collagen in both groups (p<0.001). Collagen III stabilized in the 14th day and collagen I continued to ascend. CONCLUSIONS: The gain in resistance of the polypropylene mesh is regular and ascending, whereas the polypropylene/poliglecaprone is not regular. The final resistance of both meshes is similar; the collagen density increases over time, and show the same inflammatory potential.

The Role of Collagen Metabolism in the Formation and Relapse of Incisional Hernia.

Despite the continuous development of synthetic prosthetic meshes and their wide use, recurrent incisional hernias still appear in 5 to 20% of cases, with a linear incidence curve over the years, suggesting a multifactorial process rather than a simple failing technical repair as the underlying cause. Recent molecular biological research provide increasing evidence of connective tissue alterations such as a defective wound healing with impaired scarring process in patients with incisional hernia. Although there are some promising results, at present, in-depth understanding of the pathophysiological mechanisms and of the role that collagens play in the development and recurrence of incisional hernia is rather scarce. The aim of this systematic review is to summarize and evaluate the biochemical mechanisms involved in incisional hernia formation and recurrence, with a primary focus on collagen I to III ratio. Also, the consequences for surgical practice are discussed.