Vesicle Formation in Early Oral Submucous Fibrosis: Insights and Implications
Rahul Anand1, Gargi Sarode1, Namrata Sengupta1, Deepak Pandiar2, Sachin Sarode31Department of Oral Pathology and Microbiology, Dr DY Patil Dental College and Hospital, Dr DY Patil Vidyapeeth, Pune, Maharashtra, India, 2Dr DY Patil Unitech Societys, Dr DY Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra, India, 3Department of Oral Pathology and Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India,
Oral submucous fibrosis (OSF) is a chronic oral disor der characterized by the progressive fibrosis of the submucosa. OSF leads to an array of symptoms, including reduced mouth opening, burning mouth, mucosal rigidity, and exhibits potential malignant transformation.[1] OSF is considered a chronic, progressive, and potentially malig nant disorder affecting the oral mucosa, particularly the buccal mucosa, palate, and tongue. It is primarily charac terized by fibrosis or the excessive deposition of collagen f ibres in the submucosal connective tissue.[2] It is strongly associated with the habitual chewing of areca/ betel nut, which contain bioactive compounds such as arecoline, are caidine etc.[3] Vesicle formation is not a typical feature of OSF however, occasional scenarios have been reported in the literature.[4] Also, the pathogenesis of vesicle formation in OSF is not primarily associated with the clinical presen tation of the disease. The exploration of the potential pathogenesis underlying vesicle formation in the early stages of OSF constitutes a significant endeavour to unravel the intricacies of this multifaceted phenomenon. At its core, OSF represents a chronic oral disorder characterized by the progressive fi brosis of the submucosal connective tissues. However, in dications from the literature suggest a subset of early OSF cases presents with vesicle formation, which adds a novel layer to the understanding of its underlying mechanisms. [5] This phenomenon, though less prevalent compared to the more established fibrotic manifestations, necessitates a thorough examination. Initiation and Formation of Nucleation Sites A plausible pathogenesis for vesicle formation in early OSF could be speculated based on the available literature and considerations. The path to vesicle development could potentially be initiated by the consumption of areca nut, a significant risk factor for OSF leading to formation of nu cleation sites.[3] Nucleation sites are tiny imperfections or surface irregularities in localized regions where a perturba tion in the tissue integrity or cellular arrangement triggers an initial disturbance. Habitual chewing exposes the oral mucosa to constituents of the areca nut, notably arecoline, which is believed to trigger an array of cellular responses. One pivotal aspect is the potential compromise of the epithelial barrier function due to arecoline-induced damage.[6] This impairment could result in increased permeability, thereby allowing immune cells and inflammatory mediators to infiltrate the underlying oral mucosal tissues. Areca nut components have been reported to stimulate interleukin-1, interleukin-6, interleu kin-8, cyclooxygenase-2, and tumour necrosis factor- in oral epithelial cells, and salivary levels of these cytokines correlate with the severity of OSMF.[7, 8] Fluid Accumulation and Surface Tension Consequently, a localized inflammatory response may en sue, marked by the release of pro-inflammatory cytokines, chemokines, and recruitment of immune cells such as neu trophils and macrophages. These immune cells play an ac tive role in addressing the perturbation, aiming to contain and resolve the insult.[9] However, the inflammatory milieu facilitated by these cells could inadvertently contribute to the development of vesicles. The increased vascular perme ability, a consequence of the ongoing immune response, may lead to fluid leakage into the interstitial spaces, culmi nating in the formation of vesicles beneath the damaged epithelium. The vesicular formations could, therefore, be interpreted as an adaptive response to the areca nut-in duced insult. Vesicle production is significantly influenced by surface tension, a basic feature of fluids caused by intermolecular interactions at the interface between the fluid and sur rounding surfaces. The structural integrity of the mucosal layer is often maintained by elevated surface tension at the epithelial-submucosal junction. However, localised chang es in surface tension brought on by cellular interactions, immunological mediators, or molecular rearrangements may weaken this interface and permit the accumulation of f luid below the mucosal layer.Tissue Integrity, Pressure and Temperature Increased vascular permeability and the flow of immune cells and inflammatory mediators to the afflicted location cause fluid buildup underneath the mucosal layer. The col lection of fluid causes an increase in hydrostatic pressure inside the submucosal space. The submucosal layers, con strained by surrounding tissues and the epithelial layer, un dergo deformation as they attempt to accommodate the increasing volume of accumulated fluid. The mechanical stability of submucosal tissue is deter mined by its structural components, including collagen f ibres, cellular junctions, and extracellular matrix. The me chanical stress put on these structural components when pressure develops owing to fluid buildup can cause me chanical deformation, causing the tissue to stretch and swell. This deformation can further enhance the formation of sub-epithelial vesicle in the context of reduced structur al integrity. Other physical attributes like temperature can also influ ence the initiation and progression of such submucosal vesicles by influencing the kinetics of cellular and molec ular processes. Higher temperatures enhance cellular me tabolism, immune cell activity, and inflammatory medi ator release. These mechanisms can hasten fluid buildup and change the kinetics of tissue response. Furthermore, temperature-induced alterations in molecular interactions might affect surface tension, thereby leading to local epi thelial-submucosal interface weakening. Additionally, the autoimmune aspect which is increasingly recognized as a potential contributor to OSMF, could poten tially intersect with vesicle formation.[10] Chronic inflamma tion and tissue damage could stimulate the immune system to produce autoantibodies against oral mucosal antigens, thereby exacerbating vesicle formation. These autoantibod ies may contribute to the blister-like structures by targeting components of the epithelium, leading to localized separa tion of cells and fluid accumulation. Eosinophilia in the sub mucosa of OSF patients has been reported in the literature.[5] Chronic inflammation and tissue damage stimulate fibro blast activation and collagen production. Early vesicles may undergo fibrotic changes due to ongoing inflamma tion and immune response. As fibrosis progresses, the ves icles' original appearance might be altered due to collagen deposition. The fibrotic changes could obscure the initial vesicular presentation, thereby masking the clinical pre sentation. A possible mechanism behind vesicle formation in OSF has been summarized in Figure 1. However, it's crucial to acknowledge that this proposed patho genesis is speculative in nature and requires further investi gations and well-established evidence. The phenomenon of vesicle formation in early OSF warrants in-depth investigation through controlled studies, histopathological analyses, immu nological profiling, and molecular studies. Comprehensive ex ploration of this intriguing manifestation could uncover new insights into the intricate mechanisms driving the initiation of OSF and its diverse clinical presentations. The exploration of vesicle formation in early stages of OSF presents a promising avenue for understanding the disease's multifaceted pathogenesis. To elucidate this phenomenon, a series of comprehensive studies should be undertaken. Epi demiological investigations on a substantial scale would as certain the prevalence and clinical characteristics of vesicle formation in early OSF cases along with histopathological analyses of mucosal biopsies which would provide insights into their histological attributes. Concurrently, immunologi cal examinations could delve into the autoimmune aspect, profiling immune cells, cytokines, and autoantibodies with in vesicle-associated tissues to unravel intricate immuno pathogenic mechanisms. Future studies, vis-ą-vis molecular investigations are also essential, focusing on the molecular pathways triggered by the areca nut constituents, particu larly arecoline, to discern their role in initiating vesicle for mation. Additionally, longitudinal studies tracking at-risk in dividuals over time would yield invaluable insights into the natural progression of vesicle-related events. In the realm of therapeutic interventions and clinical con siderations, early detection and monitoring strategies would be instrumental in identifying individuals in the ini tial stages of vesicle formation. Anti-inflammatory agents, both topical and systemic, could potentially mitigate the inflammatory response contributing to vesicle develop ment. Exploring immune-modulating medications may address the autoimmune underpinnings, potentially influ encing vesicle formation. Advanced techniques in tissue engineering could be harnessed to restore or regenerate compromised mucosal tissues, potentially preventing further vesicle occurrence. Equally important, patient ed ucation initiatives focusing on the dangers of areca nut chewing and behaviour modification are needed to raise awareness and influence cessation decisions. Rigorous clin ical trials, employing placebo-controlled designs, would offer empirical evidence of the efficacy and safety of ther apeutic interventions targeting early vesicle formation. A multi-disciplinary approach, involving oral health profes sionals, dermatologists, and immunologists, could foster comprehensive care for early OSF cases. In conclusion, an in-depth investigation into the occur rence of vesicle formation in early stages of OSF holds tre mendous promise for unravelling intricate aspects of the disease's pathogenesis. By conducting rigorous studies encompassing epidemiology, histopathology, immunolo gy, and molecular pathways, a comprehensive understand ing of this phenomenon could be achieved. Furthermore, translating insights into potential therapeutic strategies and clinical considerations could usher in a new era of tai lored management approaches for OSF patients.
Cite This Article
Anand R, Sarode G, Sengupta N, Pandiar D, Sarode S. Vesicle Formation in Early Oral Submucous Fibrosis: Insights and Implications. EJMO. 2024; 8(1): 110-112
Corresponding Author: Rahul Anand