Balanite Xerotica Obliterans in età pediatrica :meccanismi di danno biomolecolare e ricerca di strategie farmacologiche innovative

AIM : Balanitis xerotica obliterans (BXO) is a chronic inflammatory skin disorder of unclear etiology, it is considered the male genital variant of lichen sclerosus. The etiology and the exact molecular mechanisms underlying the disease are still unknown. The histopathology of BXO is characterized by alterations in the epidermis and dermis as well as inflammatory cell infiltration. In this regard several factors may be involved in underling molecular changes associated with inflammatory response. Antiinflammatory drugs are commonly used in pre-operative setting to decrease the inflammatory/autoimmune response and for proper wound healing. Olive Oil Ozonides are used in several medical applications for its anti-inflammatory, anti-microbial and skin restoring properties. The human Transglutaminases (TGs) family consists of several proteins with catalytic activity essential for biological processes such as skin barrier formation and extracellular matrix assembly but can also contribute to the pathophysiology of various inflammatory , autoimmune and degenerative conditions. Given the key role played by TGs in the maintenance of epidermis integrity and extracellular matrix stability, the aim of this study was to investigate transcript levels of three TGs in foreskin of children underwent to surgery for phimosis without or with histologically confirmed BXO, to characterize the relationship between changes of TG levels and BXO and furthermore we evaluated the anti-inflammatory effects of treatment by assessing their effects on foreskin of patients with BXO. M&M. Thirty children with acquired phimosis were enrolled. The removed foreskins were sent both for the histological diagnosis and for the analysis of transcript levels of keratinocyte TG (TG1), tissue TG (TG2), epidermal TG (TG3) and IFN-γ, these were evaluated by quantitative Real-Time PCR .Furthermore, fifteen patients with BXO and previously treated by pediatrician with topical olive oil ozonides were compared with fifteen without any treatment. The foreskins were used to evaluate the transcript levels of pro-inflammatory cytokines, transglutaminase 2 (TG2), inducible nitric oxide synthase (NOS2), enzymes involved in the inflammatory process, as well as Vascular endothelial growth factor (VEGF) by Real-Time PCR. Results. We observed a significant increase in IFN-γ and TG2 mRNA levels by 2.8 and 2.9 folds (p<0.001), respectively, and a decrease in TG1 and TG3 transcripts by about 70% (p<0.001) in foreskin from patients with BXO (n=15) in comparison with patients without BXO (n=15). We observed a reduction by about 70% (p<0.001) in mRNA levels of cytokines, such IL-1β, TNF-α and INF–γ, as well as a decrease higher than 90% (p<0.001) in TG2 and NOS2 gene transcripts in tissues from Ozonides group. We also found an increase of 17 folds (p<0.001) in VEGF transcript in tissues treated with ozonides in comparison to untreated patients. Conclusion The reduced expression of TG1 and TG3 is associated with altered structure of foreskin in BXO and can be a consequence of damage to keratinocytes. Increased expression of TG2 and IFN-γ can be the result of chronic inflammation. TG2 overexpression can play a pivotal role in triggering and maintaining the inflammatory response in BXO patients. Our results suggest that pre-operatory treatment with Ozonides could provide a considerable benefit in terms of reduction of the inflammatory response in tissues with BXO. Additionally, the increased production of VEGF could stimulate a faster recovery and promote the healing process in patients undergoing surgery