Materiały źródłowe

• #1 Pathogenesis of nasal polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4422388/

  Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition that affects a large proportion of the population world-wide and is associated with high cost of management and significant morbidity. […] The mechanisms that drive pathogenesis in this disease remain unclear. […] Defects in the innate function of the airway epithelial barrier, including diminished expression of antimicrobial products and loss of barrier integrity, combined with colonization by fungi and bacteria likely play a critical role in the development of chronic inflammation in CRSwNP. […] This chronic inflammation is characterized by elevated expression of many key inflammatory cytokines and chemokines, including IL-5, thymic stromal lymphopoietin and CCL11, that help to initiate and perpetuate this chronic inflammatory response.

• #2 Nasal Polyps – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560746/

  Nasal polyps are benign, inflammatory outgrowths of the sinonasal mucosa that can lead to chronic nasal obstruction, congestion, and diminished quality of life. […] The condition is multifactorial, involving persistent mucosal inflammation, immune dysregulation, and epithelial barrier dysfunction. […] In the Western Hemisphere, most cases of nasal polyps are the result of T-helper 2 (Th2) cell-driven eosinophilia and immunoglobulin E (IgE) inflammation, characterized by elevated interleukin-5 (IL-5). […] Additional proposed mechanisms include a fungi-driven inflammatory process and an exaggerated immune response to exotoxins from Staphylococcus aureus. […] The pathophysiology of nasal polyps is varied. Aging leads to anatomical and functional changes that promote the stasis of thick mucus and impair the clearance of irritants and biological offenders, such as viruses, bacteria, and fungi, thereby increasing susceptibility to polyp formation.

• #3

  https://link.springer.com/article/10.1007/s12070-022-03247-2

  Chronic Rhinosinusitis (CRS) is characterized by edema of the sub-epithelial layers, but, only specific types of CRS are developing polyps. […] Currently, we approach nasal polyposis, in terms of diagnosis and treatment, according to its endotype, which means that we focus on the specific cells and cytokines that are participating in its pathogenesis. […] It appears that the molecular procedures that contribute to polyp formation, initiating with a Th-2 response of the adaptive immune system, are local phenomena occurring in the sub-epithelial layers of the mucosa. […] Several hypotheses are trying to approach the etiology that drives the immune response towards Th-2 type. […] Currently, the most complete theory is that of epithelial immune barrier dysfunction. […] Th2 cytokines, subsequently, induce the accumulation of eosinophils and IgE together with the remodeling of the stroma in the sub-epithelial layers leading, eventually, to the formation of nasal polyps.

• #4

  https://link.springer.com/article/10.1007/s12070-022-03247-2

  In the nasal polyps, a characteristic elevation of IgE is detected. […] Tissue stroma remodeling in the lamina propria occurs, mainly, by the formation of a net created by Fibrin, produced by fibroblasts, and FXIII-A factor, produced by macrophages. […] The most current trend, for the pathogenesis of nasal polyposis approach, is the epithelial immune barrier hypothesis which combines the intrinsic and extrinsic theories. […] According to this theory, a defective epithelial barrier and a dysfunctional repair system of damaged mucosa, render the sub-epithelial layer- lamina propria- more vulnerable to invasion by pathogens. […] Overall, the idiopathic nasal polyposis in western populations does not seem to have a typical allergic background. […] Several theories are explaining the etiology that skews the immune response towards Th-2. […] Finally, the most current theory that combines all the other pathogenetic mechanisms is that of the epithelial immune barrier dysfunction.

• #5 Frontiers | Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1139240/full

  Chronic rhinosinusitis (CRS) is a clinical syndrome primarily characterized by long-term mucosal inflammation of the nasal cavity and sinuses. The pathogenesis of CRS is still unclear due to its high heterogeneity. […] A number of factors have been found to be associated with the onset and development of CRS, including geographical and racial factors, environmental exposures, sinus microbiota dysbiosis, mucociliary clearance (MCC) dysfunction, epithelial barrier impairment, and disrupted immune response. […] Essentially, the sinonasal epithelium plays a key role in both innate and adaptive immunity. However, abnormal capability of the epithelium can have a significant impact on the onset and development of CRS. Epithelial-to-mesenchymal transition (EMT), mucosal remodeling, and autophagy have been commonly observed in CRS, presenting new insight into sinonasal epithelium malfunction; these phenomena might have some connection with the pathogenesis of this disease.

• #6 Pathogenesis of nasal polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4422388/

  Importantly, however, future studies are needed to demonstrate the necessity and sufficiency of these potential drivers of disease in CRSwNP. […] It has been well documented that the upper airways or sinuses of patients with CRSwNP are often chronically colonized with fungi and bacteria and that these microbes may play an important role in CRSwNP pathogenesis. […] Although there are numerous hypothetical mechanisms that could account for this colonization, it is not yet clear whether this accumulation of microbes is an initial cause of CRSwNP or a downstream effect of the underlying inflammatory disease mechanism. […] Defects in the sinonasal epithelial barrier of patients with CRSwNP have also been documented. […] These include diminished expression, or mislocalization, of tight junction proteins and increased epithelial permeability.

• #7 Frontiers | Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1139240/full

  The presence of a normal epithelium is fundamental for maintaining homeostasis in the nasal and paranasal sinuses. Here, we describe various aspects of the sinonasal epithelium and highlight the contributions of epithelial dysfunction to CRS pathogenesis. […] The physical-mechanical barrier consists of tight junctions (TJs), adherens junctions, gap junctions, desmosomes, and hemidesmosomes; these components facilitate strong cell–cell contact, form a tight barrier, establish cell polarity, and can effectively regulate the mobility of different ions and molecules. […] Interestingly, some studies have observed significantly decreased expression of ZO-1, occludin, claudin-1, JAM-1, DSG1, and DSG2 in the primary epithelial cells of CRS patients as compared with those of healthy controls. […] Patients with CRSwNP exhibit reduced TER, which could be associated with epithelial barrier damage.

• #8 Frontiers | Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1139240/full

  The interaction of the airway epithelial cells with airborne environmental pollution and bacterial toxins is critical in the impairment of epithelial barrier function. […] When the integrity of the epithelium is destroyed, epithelial permeability can effectively increase. Invading exogenous irritants can thus activate the immune cells and thereby initiate an immune response. […] Mucociliary dysfunction can weaken protection of the nasal mucosa and has been found to be conducive to bacterial colonization, biofilm formation, and mucositis, which is a non-negligible factor in CRS pathogenesis. […] Epithelial-derived cytokines TSLP, IL-25, and IL-33 can promote the production of different Th2 cytokines, such as IL-4, IL-5, and IL-13, by activating Th2 cells as well as group 2 innate lymphoid cells (ILC2s), thus further inducing type 2 inflammatory responses.

• #9 Pathogenesis of chronic rhinosinusitis with nasal polyps: role of IL-6 in airway epithelial cell dysfunction | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02309-9

  Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by an alteration in airway epithelial cell functions including barrier function, wound repair mechanisms, mucociliary clearance. The mechanisms leading to epithelial cell dysfunction in nasal polyps (NPs) remain poorly understood. […] Our hypothesis was that among the inflammatory cytokines involved in NPs, IL-6 could alter epithelial repair mechanisms and mucociliary clearance. […] The up-regulated epithelial cell proliferation observed in polyps could be induced by IL-6 in the case of prior epithelial damage. IL-6 could be a major cytokine in NP physiopathology. […] However, restoring the integrity of the epithelial barrier after injury is also a key element in the defence capabilities of the respiratory epithelium. Dysfunction of repair of the epithelial barrier has been implicated in the pathogenesis of NPs.

• #10 Nasal Polyps – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560746/

  Nasal polyps are benign, inflammatory outgrowths of the sinonasal mucosa that can lead to chronic nasal obstruction, congestion, and diminished quality of life. […] The condition is multifactorial, involving persistent mucosal inflammation, immune dysregulation, and epithelial barrier dysfunction. […] In the Western Hemisphere, most cases of nasal polyps are the result of T-helper 2 (Th2) cell-driven eosinophilia and immunoglobulin E (IgE) inflammation, characterized by elevated interleukin-5 (IL-5). […] Additional proposed mechanisms include a fungi-driven inflammatory process and an exaggerated immune response to exotoxins from Staphylococcus aureus. […] The pathophysiology of nasal polyps is varied. Aging leads to anatomical and functional changes that promote the stasis of thick mucus and impair the clearance of irritants and biological offenders, such as viruses, bacteria, and fungi, thereby increasing susceptibility to polyp formation.

• #11

  https://link.springer.com/article/10.1007/s12070-022-03247-2

  The adaptive immune system is the cornerstone of nasal polyps pathogenesis. […] When T-nave lymphocytes become Th2, they produce IL-4, IL-5, and IL-13. […] In the context of chronic rhinitis, when polyps are formed, among the four different types of T-helper cells, we usually detect a Th2 immune response characterized by the presence of eosinophils in the sub-epithelial layer of the mucosa. […] When a Th2 immune response occurs, in the context of chronic rhinitis, in lamina propria, then several molecular reactions are taking place, including accumulation of immune cells, antibodies, and molecules that induce remodeling of the tissue stroma. […] A key event during a Th2 immune response is that lamina propria becomes congested with activated eosinophils. […] During a Th-2 immune response, chemotaxis of macrophages, Basophils, Mast cells, and fibroblasts in lamina propria is taking place.

• #12 Frontiers | Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1139240/full

  The interaction of the airway epithelial cells with airborne environmental pollution and bacterial toxins is critical in the impairment of epithelial barrier function. […] When the integrity of the epithelium is destroyed, epithelial permeability can effectively increase. Invading exogenous irritants can thus activate the immune cells and thereby initiate an immune response. […] Mucociliary dysfunction can weaken protection of the nasal mucosa and has been found to be conducive to bacterial colonization, biofilm formation, and mucositis, which is a non-negligible factor in CRS pathogenesis. […] Epithelial-derived cytokines TSLP, IL-25, and IL-33 can promote the production of different Th2 cytokines, such as IL-4, IL-5, and IL-13, by activating Th2 cells as well as group 2 innate lymphoid cells (ILC2s), thus further inducing type 2 inflammatory responses.

• #13 Tezspire met both co-primary endpoints in the Phase III WAYPOINT trial in patients with chronic rhinosinusitis with nasal polyps

  https://www.astrazeneca.com/media-centre/press-releases/2024/tezspire-nasal-polyps-trial-met-primary-endpoints.html

  Chronic rhinosinusitis with nasal polyps negatively impact patients daily lives with obstructions leading to disturbances in smell, taste and sleep as well as pain and fatigue. […] Epithelial dysfunction and inflammation are important characteristics of chronic rhinosinusitis and impede the ability of the epithelium to act as a physical and immunological barrier against the external environment. […] Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine that has been implicated in shared pathophysiological processes underlying severe asthma and CRSwNP. […] TSLP is released in response to multiple triggers (including allergens, viruses and other airborne particles) associated with asthma, CRSwNP, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE) and other diseases.

• #14 Mechanism of Action in Nasal Polyps (CRSwNP) | DUPIXENT® (dupilumab)

  https://www.dupixenthcp.com/crswnp/about/mechanism-of-action

  DUPIXENT inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4 receptor alpha (IL-4R) subunit. Blocking IL-4R with DUPIXENT inhibits IL-4 and IL-13-induced inflammatory responses, including mucosal IgE production, and lowers total IgE in the blood of patients with CRSwNP, thereby demonstrating both local and systemic effects of DUPIXENT on these markers of type 2 inflammation in CRSwNP. […] IL-4 and IL-13 are type 2 cytokines that play key roles in CRS with NP, including Th2 cell differentiation, eosinophil trafficking, and B-cell switching to IgE release. […] The mechanism of dupilumab action has not been definitively established. […] In the inflammatory process, IL-4 binds to the IL-4 receptor alpha subunit at the type 1 receptor, and IL-13 binds to the IL-13 receptor alpha 1 subunit at the type 2 receptor. IL-4 can also bind to the IL-4 receptor alpha subunit at the type 2 receptor, and each interaction transmits its own signal downstream. DUPIXENT binds to IL-4 receptor alpha subunit, blocking IL-4 and IL-13 intracellular signaling. This results in reduced expression of pro-inflammatory cytokines, ultimately leading to decreased total and specific IgE. In addition, there is an impact on eosinophil activation and trafficking, along with other mechanisms that decrease type 2 inflammation. DUPIXENT is the first and only dual inhibitor of IL-4 and IL-13 signaling, two cytokines that contribute to underlying type 2 inflammation in CRS with NP.

• #15 Biologics for Chronic Rhinosinusitis with Nasal Polyps | AAO-HNS Bulletin

  https://bulletin.entnet.org/clinical-patient-care/article/22881642/biologics-for-chronic-rhinosinusitis-with-nasal-polyps

  Biologics are monoclonal antibodies developed through recombinant technology. They act by targeting a specific protein considered germane in the pathogenesis of a disease. Three biologics targeting type 2 inflammation in CRSwNP have recently been approved by the U.S. Food and Drugs Administration (FDA): dupilumab, mepolizumab, and omalizumab. […] Table 1 summarizes the mechanism of action for each of the approved biologics, while Figure 1 also depicts where these biologics target nasal polyp pathogenesis. […] Dupilumab was first approved for noncontrolled moderate to severe atopic dermatitis. […] Dupilumab, mepolizumab, and omalizumab were all successful in demonstrating increased efficacy in the primary end point of decreasing the nasal polyp size. […] Three biologics targeting type 2 inflammation have recently been approved by the FDA for nasal polyps: dupilumab, mepolizumab, and omalizumab. These appear to reduce nasal polyp size and positively impact sinonasal symptoms and quality of life with varying efficacy. Many questions on the use of biologics for nasal polyps currently remain unanswered regarding the length of treatment, who benefits most, and whether biologics should be used with, without, before, or after surgery.

• #16 Pathogenesis of chronic rhinosinusitis with nasal polyps: role of IL-6 in airway epithelial cell dysfunction | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02309-9

  Our hypothesis was that among the inflammatory cytokines involved in NPs, IL-6 could alter epithelial repair mechanisms. […] In CRSwNP pathogenesis, the initial mechanism in the formation of polyps could be a rupture of both the epithelial continuity and the basement membrane. […] However, the mechanisms leading to epithelial cell dysfunction remain poorly understood. […] IL-6 was thus chosen to investigate a doseresponse effect on HNEC repair. […] This study also showed quantitative up-regulation of cell proliferation with IL-6 in the case of prior epithelial damage compared with other IL-stimulated conditions. […] While some authors suggest that IL-6 plays an important role in chronic inflammation in CRSwNP, its mechanism of action remains poorly understood. […] We also found that IL-9 did not affect goblet cell differentiation as we might have expected in view of its known role in metaplasia goblet cell induction. […] This study therefore presents the first in vitro results of an IL-6 effect on the ciliary beating in human nasal epithelial ciliated cells. […] Overall, the epithelial barrier dysfunction could be involved in physiopathology of nasal polyps.

• #17 Pathogenesis of chronic rhinosinusitis with nasal polyps: role of IL-6 in airway epithelial cell dysfunction | springermedizin.de

  https://www.springermedizin.de/pathogenesis-of-chronic-rhinosinusitis-with-nasal-polyps-role-of/17827630

  Dysfunction of repair of the epithelial barrier has been implicated in the pathogenesis of NPs. […] Our hypothesis was that among the inflammatory cytokines involved in NPs, IL-6 could alter epithelial repair mechanisms. […] This study also showed quantitative up-regulation of cell proliferation with IL-6 in the case of prior epithelial damage compared with other IL-stimulated conditions. […] IL-6 was also found to affect ciliary functions by increasing CBF and metachronal wavelength. […] The mechanisms underlying the pathogenesis of CRSwNP remain poorly defined. […] In conclusion, IL-6 trans-signaling could induce chronic proliferation of epithelial cells after wound healing of the epithelial barrier and growth of NPs.

• #18 The Morphology of Nasal Polyps in Different Age Groups: Histopathological Features

  https://www.mdpi.com/2075-4426/14/4/414

  Nasal polyps (NPs) represent the end-stage local manifestation of a chronic inflammatory disease affecting the nasal cavity and paranasal sinuses. […] NPs originate from mucosal epithelial rupture, fibrous tissue proliferation, extracellular matrix accumulation, and inflammatory cell infiltration. […] Histologically, they are characterized by an infiltration of inflammatory cells, including eosinophils, neutrophils, mast cells, plasma cells, lymphocytes, and monocytes associated with structural fibrosis, edematous stromal tissue, and basement membrane thickening. […] The presence of high levels of eosinophils has been related to the perpetuation of the inflammatory process in CRS with nasal polyps (CRSwNPs). […] Eosinophilic inflammation has been associated with more severe disease, higher rates of recurrence after surgery, and a greater likelihood of comorbid asthma and allergies.

• #19 The Morphology of Nasal Polyps in Different Age Groups: Histopathological Features

  https://www.mdpi.com/2075-4426/14/4/414

  Nasal polyps (NPs) represent the end-stage local manifestation of a chronic inflammatory disease affecting the nasal cavity and paranasal sinuses. […] NPs originate from mucosal epithelial rupture, fibrous tissue proliferation, extracellular matrix accumulation, and inflammatory cell infiltration. […] Histologically, they are characterized by an infiltration of inflammatory cells, including eosinophils, neutrophils, mast cells, plasma cells, lymphocytes, and monocytes associated with structural fibrosis, edematous stromal tissue, and basement membrane thickening. […] The presence of high levels of eosinophils has been related to the perpetuation of the inflammatory process in CRS with nasal polyps (CRSwNPs). […] Eosinophilic inflammation has been associated with more severe disease, higher rates of recurrence after surgery, and a greater likelihood of comorbid asthma and allergies.

• #20 Eosinophil Counts in Nasal Polyps (NP)

  https://eosinophilosophy.com/disease-state/nasal-polyps/

  Nasal polyps are benign, inflammatory masses that form in the nasal mucosa and paranasal sinuses as a result of chronic inflammation in the nasal passages. They are observed in a subtype of chronic rhinosinusitis, which is a chronic inflammatory condition of the nose, paranasal sinus, and upper airways, defined as having documented inflammation and 2 of the following symptoms for 12 weeks: […] Eosinophils play an important role in up to 90% of nasal polyp cases in the US and Europe. […] Eosinophils and type 2 inflammation in the pathogenesis of nasal polyps. […] Elevated eosinophils in the tissue and blood indicate eosinophil involvement in nasal polyps. […] Eosinophils contribute to nasal polyp recurrence. […] Several studies have found that patients with higher tissue eosinophils have higher recurrence rates of nasal polyps than patients with lower counts. […] Higher recurrence rates with higher eosinophil counts.

• #21

  https://link.springer.com/article/10.1007/s12070-022-03247-2

  The adaptive immune system is the cornerstone of nasal polyps pathogenesis. […] When T-nave lymphocytes become Th2, they produce IL-4, IL-5, and IL-13. […] In the context of chronic rhinitis, when polyps are formed, among the four different types of T-helper cells, we usually detect a Th2 immune response characterized by the presence of eosinophils in the sub-epithelial layer of the mucosa. […] When a Th2 immune response occurs, in the context of chronic rhinitis, in lamina propria, then several molecular reactions are taking place, including accumulation of immune cells, antibodies, and molecules that induce remodeling of the tissue stroma. […] A key event during a Th2 immune response is that lamina propria becomes congested with activated eosinophils. […] During a Th-2 immune response, chemotaxis of macrophages, Basophils, Mast cells, and fibroblasts in lamina propria is taking place.

• #22

  https://link.springer.com/article/10.1007/s12070-022-03247-2

  In the nasal polyps, a characteristic elevation of IgE is detected. […] Tissue stroma remodeling in the lamina propria occurs, mainly, by the formation of a net created by Fibrin, produced by fibroblasts, and FXIII-A factor, produced by macrophages. […] The most current trend, for the pathogenesis of nasal polyposis approach, is the epithelial immune barrier hypothesis which combines the intrinsic and extrinsic theories. […] According to this theory, a defective epithelial barrier and a dysfunctional repair system of damaged mucosa, render the sub-epithelial layer- lamina propria- more vulnerable to invasion by pathogens. […] Overall, the idiopathic nasal polyposis in western populations does not seem to have a typical allergic background. […] Several theories are explaining the etiology that skews the immune response towards Th-2. […] Finally, the most current theory that combines all the other pathogenetic mechanisms is that of the epithelial immune barrier dysfunction.

• #23 Mechanism of Action in Nasal Polyps (CRSwNP) | DUPIXENT® (dupilumab)

  https://www.dupixenthcp.com/crswnp/about/mechanism-of-action

  DUPIXENT inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4 receptor alpha (IL-4R) subunit. Blocking IL-4R with DUPIXENT inhibits IL-4 and IL-13-induced inflammatory responses, including mucosal IgE production, and lowers total IgE in the blood of patients with CRSwNP, thereby demonstrating both local and systemic effects of DUPIXENT on these markers of type 2 inflammation in CRSwNP. […] IL-4 and IL-13 are type 2 cytokines that play key roles in CRS with NP, including Th2 cell differentiation, eosinophil trafficking, and B-cell switching to IgE release. […] The mechanism of dupilumab action has not been definitively established. […] In the inflammatory process, IL-4 binds to the IL-4 receptor alpha subunit at the type 1 receptor, and IL-13 binds to the IL-13 receptor alpha 1 subunit at the type 2 receptor. IL-4 can also bind to the IL-4 receptor alpha subunit at the type 2 receptor, and each interaction transmits its own signal downstream. DUPIXENT binds to IL-4 receptor alpha subunit, blocking IL-4 and IL-13 intracellular signaling. This results in reduced expression of pro-inflammatory cytokines, ultimately leading to decreased total and specific IgE. In addition, there is an impact on eosinophil activation and trafficking, along with other mechanisms that decrease type 2 inflammation. DUPIXENT is the first and only dual inhibitor of IL-4 and IL-13 signaling, two cytokines that contribute to underlying type 2 inflammation in CRS with NP.

• #24 Frontiers | Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1139240/full

  The dysregulation of 1α-hydroxylase and vitamin D in the sinuses in CRS has been reported previously. […] The phenomenon of EMT has been observed in patients with CRS and there is also evidence that it affects patients with CRSwNP. […] Canonical Wnt signaling has been demonstrated to be activated in nasal polyps, triggering epithelial disorders such as compromised adherens junctions and reduced ciliogenesis, which can in turn stimulate cytokine release. […] Epithelial disorder is pivotal in the etiology or pathogenesis of CRS; epithelial barrier disruption and MCC dysfunction constitute the fundamental pathogenesis of CRS. […] Overall, considering the importance of sinonasal epithelium-mediated immunity disorders for CRS pathogenesis, vigorous efforts should be applied to the development of novel biological agents that can antagonize the actions of inflammatory bioactive components produced by the epithelium, maintain the immune balance of the nasal mucosa, alleviate local inflammation, and reduce nasal polyp formation.

• #25 Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

  https://www.mdpi.com/1422-0067/21/18/6878

  Chronic rhinosinusitis is a common inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia. The genetic predisposition or the exposure to irritants can sustain the inflammatory response and the development of nasal polyposis. Nasal polyps are benign and teardrop-shaped growths that project in the nasal cavities, and originate from the ethmoid sinuses. This inflammatory process is associated with high expression of IL-4, IL-5 and IL-13 and IgE. Antibodies targeting these cytokines or receptors represent a therapeutic strategy in the treatment of nasal polyposis in combination with corticosteroids. The molecular pathogenesis of nasal polyps in chronic rhinosinusitis (CRS) patients is associated with remodeling transition, a process in which epithelial cells lose their typical phenotype, acquiring a mesenchymal-like aspect. TGFβ/SMAD, ERK, and Wnt/β-catenin pathways are altered during the nasal tissue remodeling. miRNA and inhibitor molecules targeting these signaling pathways are able to interfere with the process; which could lead to alternative therapies. Nasal polyps are an alternative source of mesenchymal stem cells, which can be isolated from surgical biopsies. A molecular understanding of the biology of PO-MSCs will contribute to the delineating inflammatory process underlying the development of nasal polyps.

• #26 Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

  https://www.mdpi.com/1422-0067/21/18/6878

  TGF-β1-signaling dysregulation is found in inflammatory polyps where it participates to sustain the characteristic remodeling of nasal mucosa. Down-regulation of TGF-β1 is typically associated with CRSwNP, whereas TGF-β1 up-regulation is characteristic of CRSsNP. TGF-β1 signaling acts as a potent driver in EMT during nasal polyp formation and growth, inducing a loss of epithelial and gain of mesenchymal markers, verified by TSA, HDAC 1/2 inhibitor. […] Epithelial mesenchymal transition (EMT) is part of this complex cellular process by which, epithelial cells lose their epithelial phenotype and acquire a mesenchymal one, following a chronic stimulus. During EMT, on the one hand, epithelial markers, for example E-cadherin, are down-regulated by several inducers of EMT acting as transcription factors such as Snail, Slug, Twist, and Zeb; on the other hand, an upregulation of mesenchymal markers such as N-cadherin, alpha-smooth muscle actin (α-SMA), vimentin, and fibronectin, as well as matrix metalloproteinases (MMP) occur. […] The understanding of the different cell signal transduction pathways involved in polyp pathogenesis will give the possibility to identify novel molecular-target agents that could be used to complement current therapeutic strategies.

• #27 Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

  https://www.mdpi.com/1422-0067/21/18/6878

  The inflammatory process plays an important role in the pathogenesis of nasal polyposis. The different forms of CRS appear to be caused by inflammatory changes in the sinonasal mucosa. A Type 2 T helpers (Th2)-mediated inflammatory process is usually found in CRSwNP, whereas both Th2- and Th1-mediated processes are found in CRSsNP. […] The process of polypogenesis results in a remodeling of the nasal tissue having a weakening of cell-to-cell contacts and increase of motility. Many factors act through different intra-cellular signaling pathways regulating polypogenesis, such as TGF-β1/SMAD3, HIF-1α, AGE/RAGE/ERK, MEK1/2-ERK1/2, Wnt/β-catenin/GSK3, and PPARγ to achieve the reorganizing of the tissue. The signaling acts in coordination with inflammatory cytokines and unbalance can result in polyp formation and sustained proliferation.

• #28 Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

  https://www.mdpi.com/1422-0067/21/18/6878

  TGF-β1-signaling dysregulation is found in inflammatory polyps where it participates to sustain the characteristic remodeling of nasal mucosa. Down-regulation of TGF-β1 is typically associated with CRSwNP, whereas TGF-β1 up-regulation is characteristic of CRSsNP. TGF-β1 signaling acts as a potent driver in EMT during nasal polyp formation and growth, inducing a loss of epithelial and gain of mesenchymal markers, verified by TSA, HDAC 1/2 inhibitor. […] Epithelial mesenchymal transition (EMT) is part of this complex cellular process by which, epithelial cells lose their epithelial phenotype and acquire a mesenchymal one, following a chronic stimulus. During EMT, on the one hand, epithelial markers, for example E-cadherin, are down-regulated by several inducers of EMT acting as transcription factors such as Snail, Slug, Twist, and Zeb; on the other hand, an upregulation of mesenchymal markers such as N-cadherin, alpha-smooth muscle actin (α-SMA), vimentin, and fibronectin, as well as matrix metalloproteinases (MMP) occur. […] The understanding of the different cell signal transduction pathways involved in polyp pathogenesis will give the possibility to identify novel molecular-target agents that could be used to complement current therapeutic strategies.

• #29 Frontiers | Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1139240/full

  The dysregulation of 1α-hydroxylase and vitamin D in the sinuses in CRS has been reported previously. […] The phenomenon of EMT has been observed in patients with CRS and there is also evidence that it affects patients with CRSwNP. […] Canonical Wnt signaling has been demonstrated to be activated in nasal polyps, triggering epithelial disorders such as compromised adherens junctions and reduced ciliogenesis, which can in turn stimulate cytokine release. […] Epithelial disorder is pivotal in the etiology or pathogenesis of CRS; epithelial barrier disruption and MCC dysfunction constitute the fundamental pathogenesis of CRS. […] Overall, considering the importance of sinonasal epithelium-mediated immunity disorders for CRS pathogenesis, vigorous efforts should be applied to the development of novel biological agents that can antagonize the actions of inflammatory bioactive components produced by the epithelium, maintain the immune balance of the nasal mucosa, alleviate local inflammation, and reduce nasal polyp formation.

• #30 Pathogenesis of nasal polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4422388/

  Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition that affects a large proportion of the population world-wide and is associated with high cost of management and significant morbidity. […] The mechanisms that drive pathogenesis in this disease remain unclear. […] Defects in the innate function of the airway epithelial barrier, including diminished expression of antimicrobial products and loss of barrier integrity, combined with colonization by fungi and bacteria likely play a critical role in the development of chronic inflammation in CRSwNP. […] This chronic inflammation is characterized by elevated expression of many key inflammatory cytokines and chemokines, including IL-5, thymic stromal lymphopoietin and CCL11, that help to initiate and perpetuate this chronic inflammatory response.

• #31 Nasal Polyps – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560746/

  Nasal polyps are benign, inflammatory outgrowths of the sinonasal mucosa that can lead to chronic nasal obstruction, congestion, and diminished quality of life. […] The condition is multifactorial, involving persistent mucosal inflammation, immune dysregulation, and epithelial barrier dysfunction. […] In the Western Hemisphere, most cases of nasal polyps are the result of T-helper 2 (Th2) cell-driven eosinophilia and immunoglobulin E (IgE) inflammation, characterized by elevated interleukin-5 (IL-5). […] Additional proposed mechanisms include a fungi-driven inflammatory process and an exaggerated immune response to exotoxins from Staphylococcus aureus. […] The pathophysiology of nasal polyps is varied. Aging leads to anatomical and functional changes that promote the stasis of thick mucus and impair the clearance of irritants and biological offenders, such as viruses, bacteria, and fungi, thereby increasing susceptibility to polyp formation.

• #32 Chronic rhinosinusitis with nasal polyps is characterized by dysbacteriosis of the nasal microbiota | Scientific Reports

  https://www.nature.com/articles/s41598-018-26327-2

  Chronic rhinosinusitis with nasal polyps (CRSwNP) is defined as a subgroup of chronic rhinosinusitis (CRS) that is characterized by the presence of fleshy swellings (nasal polyps) that develop in the lining of the nose and paranasal sinuses. Nasal polyps (NP) are believed to arise in the nasal mucosa because of chronic inflammation. […] The definitive mechanisms underlying the pathogenesis of CRS remain poorly elucidated. Microbial involvement have been considered to be one of the mechanisms contributing to the inflammation in case of CRS. […] Our group has previously demonstrated that Staphylococcus aureus is able to drive Th2 type inflammation and that it is associated with Th2-biased CRSwNP. […] We reasoned that a study with well-defined subgroups of CRS patients could possibly identify different microbiota, which might be related to specific pathological or immunological characteristics of the inflammation.

• #33 Nasal polyposis | PPT

  https://www.slideshare.net/slideshow/nasal-polyposis-231903144/231903144

  Krajina found in cases of chronic infection or allergy localized infiltrates in the nasal mucosa and localized hyperplasia of nasal glands. The glands will increase in size and cause bulging of the mucosa. […] In the initial stage of polyp formation, an epithelial rupture or necrosis caused by inflammation and tissue pressure from the edematous and infiltrated lamina propria takes place. Lamina propria protrudes through the epithelial defect, and the adjacent epithelium tends to cover the defect by migrating from the surroundings. […] A possible intrinsic defect in PGE2 production might, therefore, be responsible for a further increase of eosinophilic accumulation in ASA intolerant patients. […] Multiclonal IgE antibody formation to Staphylococcus aureus enterotoxins can be seen in nasal polyp tissue, but rarely in CRS. It is positive in about 30-50% of the patients with NP and in about 60-80% of nasal polyp subjects with asthma.

• #34 Chronic rhinosinusitis with nasal polyps is characterized by dysbacteriosis of the nasal microbiota | Scientific Reports

  https://www.nature.com/articles/s41598-018-26327-2

  This study identifies that the relative abundance of H. influenzae is remarkably higher in CRSwNP cases compared to normal subjects. […] The abundance of E. coli in several CRSwNP+A patients and the positive correlation of E. coli with ECP and IL-5 suggest a role of E. coli in severity of type 2 inflammation in CRSwNP patients. […] It is possible that E. coli impairs the epithelial barrier and cooperates with putative pathogens for initiation and amplification of type 2 inflammation in CRSwNP disease. […] The presence of specific IgE to staphylococcal enterotoxins (SE-IgE) is significantly more frequent in the CRSwNP+A compared to the CRSwNPA and control groups and correlates with disease severity. […] The functions of microbiota and their products in health and airway disease should be further elucidated to determine the effective role of microbiota in the pathomechanism of CRS disease.

• #35 Roundup: Pathogenesis and Prognosis of CRSwNP, CRSsNP, and AERD | Consultant360

  https://www.consultant360.com/exclusive/consultant360/nasal-polyps/roundup-pathogenesis-and-prognosis-crswnp-crssnp-and-aerd

  A recent review of published literature on B cells and antibodies outlines their possible role in the disease pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Evidence supports that the pathogenesis of CRSwNP and aspirin-exacerbated respiratory disease (AERD) relies on local activation of B cells and antibody production. […] The researchers conducted postoperative follow-ups with patients with CRSwNP for 1 year. They found an association between microbial dysbiosis in the nasal cavity and the pathogenesis of CRSwNP. […] The recurrence of nasal polyps after endoscopic sinus surgery may be potentially related to the decrease in protective bacteria and the increase in pathogenic bacteria, and the improvement of postoperative bacterial disorder is correlated with the nonrecurrence of CRSwNP, the researchers concluded.

• #36 Nonsurgical Treatment of Nasal Polyps: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/861353-overview

  Nasal polyposis results from chronic inflammation of the nasal and sinus mucous membranes. Chronic inflammation causes a reactive hyperplasia of the intranasal mucosal membrane, which results in the formation of polyps. The precise mechanism of polyp formation is incompletely understood. […] In 1990, Tos reported 10 pathogenic theories of nasal polyp formation: Adenoma and fibroma theories, Necrosing ethmoiditis theory, Glandular cyst theory, Mucosal exudate theory, Cystic dilatation of the excretory duct and vessel obstruction theory, Blockade theory, Periphlebitis and perilymphangitis theory, Glandular hyperplasia theory, Gland new formation theory, Ion transport theory. […] Multiple chemical mediators have been identified in nasal polyps but their significance has not been completely elucidated. Some of these mediators may be released by the polyps themselves and others by the eosinophils found in certain subsets of polyps. Cysteinyl leukotriene receptors and interleukin-5 (IL-5) appear to be the most well studied.

• #37 Nasal Polyps: etiology,pathogenesis,clinical features,management | PPT

  https://www.slideshare.net/slideshow/nasal-polyps-etiologypathogenesisclinical-featuresmanagement/233057653

  Nasal polyps are sacs of edematous nasal mucosa that can cause nasal obstruction. […] Theories of pathogenesis include adenoma fibroma theory, necrotizing ethmoiditis, glandular hyperplasia, and epithelial rupture theory. […] Virchow Nasal polypi were primary tumors like myxomas. […] Eggston Wolff Nasal polypi were caused by passive oedema of nasal mucosa. […] Billroth Microscopically nasal polypi resembled nasal mucosa. Suggested that hypertrophied nasal mucosa could be the cause. […] Kern Shenck allergy was common among patients with nasal polypi. […] Burns theory Acid mucopolysaccharide theory. […] Lurie Association between nasal polyposis and cystic fibrosis. […] Samters triad Aspirin sensitivity, nasal polypi and bronchial asthma. […] Adenoma fibroma theory of Billroth Large number of tubular glands seen in polypoidal tissue Increase in the number of these glands causing adenomatous change could be the cause for nasal polyposis.

• #38 Nasal Polyps: etiology,pathogenesis,clinical features,management | PPT

  https://www.slideshare.net/slideshow/nasal-polyps-etiologypathogenesisclinical-featuresmanagement/233057653

  Epithelial rupture theory Current Epithelial rupture due to tissue oedema Prolapse of lamina propria through the defect. […] Nasal obstruction Unilateral / bilateral Anosmia Loss of taste Rhinorrhoea watery / mucoid / mucopurulent Head ache Broadening of nose (Frog face). […] Smooth glossy multiple mass seen in anterior rhinoscopy Insensitive on probing. […] Polypectomy Endoscopic polypectomy Caldwel Luc procedure External ethmoidectomy.

• #39 A family-based genome-wide association study of chronic rhinosinusitis with nasal polyps implicates several genes in the disease pathogenesis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185244

  The pathogenesis of chronic rhinosinusitis with nasal polyps is largely unknown. […] Our study indicates that HLCS, HLA-DRA, BICD2, VSIR and SLC5A1 could be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. […] This study suggests that HLA-DRA as well as four additional genes; HLCS, VSIR, BICD2 and SLC5A1, which have not been previously identified as associated with chronic rhinosinusitis with nasal polyps, could be important for the development of this disease.

• #40 Researchers Trying to Zero In on Nasal Polyps Find Target Elusive – Page 9 of 9 – ENTtoday

  https://www.enttoday.org/article/researchers-trying-to-zero-in-on-nasal-polyps-find-target-elusive/9/?singlepage=1

  Inherited genetic variation appears to be critical but yet still largely unexplained, Dr. Wang said in his presentation. Identifying the causal genes and variants in nasal polyposis is important in the path toward improved prevention, diagnosis, and treatment of nasal polyps. […] Our data suggest that AP-1 and its related gene network are central molecular effecters of epithelial damage and repair, which can be modulated by glucocorticoid treatment, he continued.

• #41 Pediatric Nasal Polyps: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/994274-overview

  Patients with CF have a defective small chloride conductance channel, regulated by cyclic adenosine monophosphate (cAMP), which causes abnormal chloride transport across the apical cell membrane of epithelial cells. The pathogenesis of nasal polyposis in patients with CF could be associated with this defect.

• #42 Nasal polyp – Wikipedia

  https://en.wikipedia.org/wiki/Nasal_polyp

  Nasal polyps are noncancerous growths within the nose or sinuses. […] The exact cause is unclear. They may be related to chronic inflammation of the lining of the sinuses. […] The true cause of nasal polyps is unknown, but they are thought to be due to recurrent infection or inflammation. Polyps arise from the lining of the sinuses. Nasal mucosa, particularly in the region of middle meatus becomes swollen due to collection of extracellular fluid. This extracellular fluid collection causes polyp formation and protrusion into the nasal cavity or sinuses. […] In people with nasal polyps due to aspirin or NSAID sensitivity, the underlying mechanism is due to disorders in the metabolism of arachidonic acid. Exposure to cycloxygenase inhibitors such as aspirin and NSAIDs leads to shunting of products through the lipoxygenase pathway leading to an increased production of products that cause inflammation.

• #43

  https://med.uth.edu/orl/2009/08/12/role-anti-leukotriene-agents-management-chronic-rhinosinusitis-nasal-polyps/

  Leukotrienes are cytokines that are made from arachidonic acid in the presence of 5-lipoxygenase. This pathway is present in various leukocytes including mast cells, neutrophils, eosinophils and monocytes. When released, the leukotrienes bind to cysteinyl-leukotriene receptors located on the cell surface of target cells. Two receptors, known as CysLT1 and CysLT2, have been identified. These receptors are thought to mediate eosinophil recruitment, bronchospasm, vasoconstriction, mucus secretion and plasma exudation. […] Given the role of leukotrienes in the recruitment of eosinophils and association with recurrence of nasal polyposis, it is reasonable to hypothesize a beneficial effect of the addition of montelukast in the management of CRS with nasal polyps. […] Histologically, chronic rhinosinusitis with nasal polyps is characterized by an abundance of eosinophils and inflammatory changes. Klapan et al, (1994) analyzed the levels of leukotrienes in the nasal mucosa of patients with sinonasal polyps and compared it non-CRS patients. They found statistically higher levels of leukotriene C4 (LTC4) in patients with recurrent sinonasal polyps after surgery as compared to healthy controls. Higher LTC4 levels were associated with risk of recurrence of nasal polyps. […] In conclusion, anti-leukotriene agents represent an alternative class of medications that can be utilized in patients with CRS with nasal polyps with allergic rhinitis and/or asthma.

• #44 Nasal Polyps: Symptoms, Causes and Treatment | MedPark Hospital

  http://www.medparkhospital.com/en-US/disease-and-treatment/nasal-polyps

  Nasal polyps can occur in individuals of any age but are more prevalent among young and middle-aged adults. […] The cause of nasal polyps is not clear due to the complexity of the causative mechanism. However, research suggests that people affected by nasal polyps may exhibit an abnormal immune response and distinct chemical markers in the nasal and sinus linings compared to those who do not develop polyps. These chemical markers play a signaling response role. Further investigation into this active area of study is greatly needed. […] Conditions associated with nasal polyps are allergies or infections that cause chronic inflammation in the nose. These include asthma, aspirin sensitivity, cystic fibrosis, dental infections, and vitamin D deficiency. People with a family history of nasal polyps are at higher risk than others.

• #45 The Morphology of Nasal Polyps in Different Age Groups: Histopathological Features

  https://www.mdpi.com/2075-4426/14/4/414

  Interestingly, the type of predominant inflammatory cells has been linked to their different clinical features. […] In the pediatric group, the inflammatory infiltrate presented many eosinophils mixed with lymphocytes, while in the adult population, lymphocytes and plasma cells were mainly evident. […] In the elderly population, inflammation was less evident and was associated with cavernous-like angecthatic structures with thrombotic stratification. […] Our results support the presence of histological specificities of NPs at different ages of life, providing new insight into the etiopathogenesis of NPs. […] It has been previously reported that in elderly patients, the pathogenesis of CRS, as well as NPs, is quite different, less linked with allergy and eosinophilic infiltration, and more with lower serum IgE levels, which is associated with weakened response to cytokines. […] Overall, anatomical and functional changes in the sinonasal regions during aging have been grouped under the term “presbynalis,” presumably explaining the different histological features observed in the NPs of different age groups.

• #46 The Morphology of Nasal Polyps in Different Age Groups: Histopathological Features

  https://www.mdpi.com/2075-4426/14/4/414

  Interestingly, the type of predominant inflammatory cells has been linked to their different clinical features. […] In the pediatric group, the inflammatory infiltrate presented many eosinophils mixed with lymphocytes, while in the adult population, lymphocytes and plasma cells were mainly evident. […] In the elderly population, inflammation was less evident and was associated with cavernous-like angecthatic structures with thrombotic stratification. […] Our results support the presence of histological specificities of NPs at different ages of life, providing new insight into the etiopathogenesis of NPs. […] It has been previously reported that in elderly patients, the pathogenesis of CRS, as well as NPs, is quite different, less linked with allergy and eosinophilic infiltration, and more with lower serum IgE levels, which is associated with weakened response to cytokines. […] Overall, anatomical and functional changes in the sinonasal regions during aging have been grouped under the term “presbynalis,” presumably explaining the different histological features observed in the NPs of different age groups.

• #47 Mechanism of Action in Nasal Polyps (CRSwNP) | DUPIXENT® (dupilumab)

  https://www.dupixenthcp.com/crswnp/about/mechanism-of-action

  DUPIXENT inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4 receptor alpha (IL-4R) subunit. Blocking IL-4R with DUPIXENT inhibits IL-4 and IL-13-induced inflammatory responses, including mucosal IgE production, and lowers total IgE in the blood of patients with CRSwNP, thereby demonstrating both local and systemic effects of DUPIXENT on these markers of type 2 inflammation in CRSwNP. […] IL-4 and IL-13 are type 2 cytokines that play key roles in CRS with NP, including Th2 cell differentiation, eosinophil trafficking, and B-cell switching to IgE release. […] The mechanism of dupilumab action has not been definitively established. […] In the inflammatory process, IL-4 binds to the IL-4 receptor alpha subunit at the type 1 receptor, and IL-13 binds to the IL-13 receptor alpha 1 subunit at the type 2 receptor. IL-4 can also bind to the IL-4 receptor alpha subunit at the type 2 receptor, and each interaction transmits its own signal downstream. DUPIXENT binds to IL-4 receptor alpha subunit, blocking IL-4 and IL-13 intracellular signaling. This results in reduced expression of pro-inflammatory cytokines, ultimately leading to decreased total and specific IgE. In addition, there is an impact on eosinophil activation and trafficking, along with other mechanisms that decrease type 2 inflammation. DUPIXENT is the first and only dual inhibitor of IL-4 and IL-13 signaling, two cytokines that contribute to underlying type 2 inflammation in CRS with NP.

• #48 Biologics for Chronic Rhinosinusitis with Nasal Polyps | AAO-HNS Bulletin

  https://bulletin.entnet.org/clinical-patient-care/article/22881642/biologics-for-chronic-rhinosinusitis-with-nasal-polyps

  Biologics are monoclonal antibodies developed through recombinant technology. They act by targeting a specific protein considered germane in the pathogenesis of a disease. Three biologics targeting type 2 inflammation in CRSwNP have recently been approved by the U.S. Food and Drugs Administration (FDA): dupilumab, mepolizumab, and omalizumab. […] Table 1 summarizes the mechanism of action for each of the approved biologics, while Figure 1 also depicts where these biologics target nasal polyp pathogenesis. […] Dupilumab was first approved for noncontrolled moderate to severe atopic dermatitis. […] Dupilumab, mepolizumab, and omalizumab were all successful in demonstrating increased efficacy in the primary end point of decreasing the nasal polyp size. […] Three biologics targeting type 2 inflammation have recently been approved by the FDA for nasal polyps: dupilumab, mepolizumab, and omalizumab. These appear to reduce nasal polyp size and positively impact sinonasal symptoms and quality of life with varying efficacy. Many questions on the use of biologics for nasal polyps currently remain unanswered regarding the length of treatment, who benefits most, and whether biologics should be used with, without, before, or after surgery.

• #49 Biologics for Chronic Rhinosinusitis with Nasal Polyps | AAO-HNS Bulletin

  https://bulletin.entnet.org/clinical-patient-care/article/22881642/biologics-for-chronic-rhinosinusitis-with-nasal-polyps

  Biologics are monoclonal antibodies developed through recombinant technology. They act by targeting a specific protein considered germane in the pathogenesis of a disease. Three biologics targeting type 2 inflammation in CRSwNP have recently been approved by the U.S. Food and Drugs Administration (FDA): dupilumab, mepolizumab, and omalizumab. […] Table 1 summarizes the mechanism of action for each of the approved biologics, while Figure 1 also depicts where these biologics target nasal polyp pathogenesis. […] Dupilumab was first approved for noncontrolled moderate to severe atopic dermatitis. […] Dupilumab, mepolizumab, and omalizumab were all successful in demonstrating increased efficacy in the primary end point of decreasing the nasal polyp size. […] Three biologics targeting type 2 inflammation have recently been approved by the FDA for nasal polyps: dupilumab, mepolizumab, and omalizumab. These appear to reduce nasal polyp size and positively impact sinonasal symptoms and quality of life with varying efficacy. Many questions on the use of biologics for nasal polyps currently remain unanswered regarding the length of treatment, who benefits most, and whether biologics should be used with, without, before, or after surgery.

• #50 Mechanism of Action in Nasal Polyps (CRSwNP) | DUPIXENT® (dupilumab)

  https://www.dupixenthcp.com/crswnp/about/mechanism-of-action

  DUPIXENT inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4 receptor alpha (IL-4R) subunit. Blocking IL-4R with DUPIXENT inhibits IL-4 and IL-13-induced inflammatory responses, including mucosal IgE production, and lowers total IgE in the blood of patients with CRSwNP, thereby demonstrating both local and systemic effects of DUPIXENT on these markers of type 2 inflammation in CRSwNP. […] IL-4 and IL-13 are type 2 cytokines that play key roles in CRS with NP, including Th2 cell differentiation, eosinophil trafficking, and B-cell switching to IgE release. […] The mechanism of dupilumab action has not been definitively established. […] In the inflammatory process, IL-4 binds to the IL-4 receptor alpha subunit at the type 1 receptor, and IL-13 binds to the IL-13 receptor alpha 1 subunit at the type 2 receptor. IL-4 can also bind to the IL-4 receptor alpha subunit at the type 2 receptor, and each interaction transmits its own signal downstream. DUPIXENT binds to IL-4 receptor alpha subunit, blocking IL-4 and IL-13 intracellular signaling. This results in reduced expression of pro-inflammatory cytokines, ultimately leading to decreased total and specific IgE. In addition, there is an impact on eosinophil activation and trafficking, along with other mechanisms that decrease type 2 inflammation. DUPIXENT is the first and only dual inhibitor of IL-4 and IL-13 signaling, two cytokines that contribute to underlying type 2 inflammation in CRS with NP.

• #51 Mechanism of Action in Nasal Polyps (CRSwNP) | DUPIXENT® (dupilumab)

  https://www.dupixenthcp.com/crswnp/about/mechanism-of-action

  DUPIXENT is the first and only dual inhibitor of IL-4 and IL-13 signaling, addressing type 2 inflammation that contributes to CRSwNP. DUPIXENT inhibits IL-4 and IL-13 cytokine-induced inflammatory responses and cell signaling. These cytokines contribute to IgE production, mast cell activation, eosinophil activation and trafficking, epithelial barrier dysfunction, and Th2 cell activation.

• #52 Biologics for Chronic Rhinosinusitis with Nasal Polyps | AAO-HNS Bulletin

  https://bulletin.entnet.org/clinical-patient-care/article/22881642/biologics-for-chronic-rhinosinusitis-with-nasal-polyps

  Biologics are monoclonal antibodies developed through recombinant technology. They act by targeting a specific protein considered germane in the pathogenesis of a disease. Three biologics targeting type 2 inflammation in CRSwNP have recently been approved by the U.S. Food and Drugs Administration (FDA): dupilumab, mepolizumab, and omalizumab. […] Table 1 summarizes the mechanism of action for each of the approved biologics, while Figure 1 also depicts where these biologics target nasal polyp pathogenesis. […] Dupilumab was first approved for noncontrolled moderate to severe atopic dermatitis. […] Dupilumab, mepolizumab, and omalizumab were all successful in demonstrating increased efficacy in the primary end point of decreasing the nasal polyp size. […] Three biologics targeting type 2 inflammation have recently been approved by the FDA for nasal polyps: dupilumab, mepolizumab, and omalizumab. These appear to reduce nasal polyp size and positively impact sinonasal symptoms and quality of life with varying efficacy. Many questions on the use of biologics for nasal polyps currently remain unanswered regarding the length of treatment, who benefits most, and whether biologics should be used with, without, before, or after surgery.

• #53

  https://med.uth.edu/orl/2009/08/12/role-anti-leukotriene-agents-management-chronic-rhinosinusitis-nasal-polyps/

  Leukotrienes are cytokines that are made from arachidonic acid in the presence of 5-lipoxygenase. This pathway is present in various leukocytes including mast cells, neutrophils, eosinophils and monocytes. When released, the leukotrienes bind to cysteinyl-leukotriene receptors located on the cell surface of target cells. Two receptors, known as CysLT1 and CysLT2, have been identified. These receptors are thought to mediate eosinophil recruitment, bronchospasm, vasoconstriction, mucus secretion and plasma exudation. […] Given the role of leukotrienes in the recruitment of eosinophils and association with recurrence of nasal polyposis, it is reasonable to hypothesize a beneficial effect of the addition of montelukast in the management of CRS with nasal polyps. […] Histologically, chronic rhinosinusitis with nasal polyps is characterized by an abundance of eosinophils and inflammatory changes. Klapan et al, (1994) analyzed the levels of leukotrienes in the nasal mucosa of patients with sinonasal polyps and compared it non-CRS patients. They found statistically higher levels of leukotriene C4 (LTC4) in patients with recurrent sinonasal polyps after surgery as compared to healthy controls. Higher LTC4 levels were associated with risk of recurrence of nasal polyps. […] In conclusion, anti-leukotriene agents represent an alternative class of medications that can be utilized in patients with CRS with nasal polyps with allergic rhinitis and/or asthma.

• #54 Medical treatment of nasal polyps: a review

  https://rcm.mums.ac.ir/article_3444.html

  Nasal polyps (NP) are macroscopic edematous masses characterized by yellow and soft tissue in nasal cavity. The mechanisms responsible for polyp formation and its recurrence have not been well clarified. During the past few years, there was an increasing interest in investigating the role of leukotrienes produced by eosinophils, mast cells, monocytes and basophiles. Antileukotrienes are drugs that change the leukotriene pathway. The role of leukotrienes in asthma pathogenesis has been well established. Nasal polyps are shown to have more leukotriene C4 (LTC4) and leukotriene B4 (LTB4) than the normal nasal tissue. Besides, the presence of LTC4 in nasal polyps may be a symptom of early polyp recurrence. Cysteinyl-leukotrienes are the cause of bronchoconstriction, mucus production, mucosal edema and inflammation. Antileukotrienes are the leukotriene receptor antagonists. Two main mechanisms can limit the leukotriene action, the first one is the inhibition of the leukotriene production by 5-lipoxygenase (zileuton), the second is by using cysteinyl leukotriene receptor 1(cysLt1 receptor) antagonists (montelukast, zarlukast, panlukast). Both procedures have been shown to have a significant effect on chronic stable asthma. The exact etiology of NP is still unknown. Generally, the conditions leading to inflammation cause the NP. Polypoid tissues contain eosinophils and neutrophils. Our review shows that the antileukotrienes have beneficial effects on sinonasal polyps and they reduce the size of the polyps.

• #55 Tezspire met both co-primary endpoints in the Phase III WAYPOINT trial in patients with chronic rhinosinusitis with nasal polyps

  https://www.astrazeneca.com/media-centre/press-releases/2024/tezspire-nasal-polyps-trial-met-primary-endpoints.html

  Chronic rhinosinusitis with nasal polyps negatively impact patients daily lives with obstructions leading to disturbances in smell, taste and sleep as well as pain and fatigue. […] Epithelial dysfunction and inflammation are important characteristics of chronic rhinosinusitis and impede the ability of the epithelium to act as a physical and immunological barrier against the external environment. […] Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine that has been implicated in shared pathophysiological processes underlying severe asthma and CRSwNP. […] TSLP is released in response to multiple triggers (including allergens, viruses and other airborne particles) associated with asthma, CRSwNP, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE) and other diseases.

• #56 Tezspire met both co-primary endpoints in the Phase III WAYPOINT trial in patients with chronic rhinosinusitis with nasal polyps

  https://www.astrazeneca.com/media-centre/press-releases/2024/tezspire-nasal-polyps-trial-met-primary-endpoints.html

  Expression of TSLP is increased in these patients and has been correlated with disease severity. […] Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of exacerbations and improved disease control. […] Tezepelumab acts at the top of the inflammatory cascade and research indicates that targeting TSLP released by the airway epithelium may be a potential approach to treating diseases of the lower airways in the future.

• #57 Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

  https://www.mdpi.com/1422-0067/21/18/6878

  Chronic rhinosinusitis is a common inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia. The genetic predisposition or the exposure to irritants can sustain the inflammatory response and the development of nasal polyposis. Nasal polyps are benign and teardrop-shaped growths that project in the nasal cavities, and originate from the ethmoid sinuses. This inflammatory process is associated with high expression of IL-4, IL-5 and IL-13 and IgE. Antibodies targeting these cytokines or receptors represent a therapeutic strategy in the treatment of nasal polyposis in combination with corticosteroids. The molecular pathogenesis of nasal polyps in chronic rhinosinusitis (CRS) patients is associated with remodeling transition, a process in which epithelial cells lose their typical phenotype, acquiring a mesenchymal-like aspect. TGFβ/SMAD, ERK, and Wnt/β-catenin pathways are altered during the nasal tissue remodeling. miRNA and inhibitor molecules targeting these signaling pathways are able to interfere with the process; which could lead to alternative therapies. Nasal polyps are an alternative source of mesenchymal stem cells, which can be isolated from surgical biopsies. A molecular understanding of the biology of PO-MSCs will contribute to the delineating inflammatory process underlying the development of nasal polyps.

• #58 Pathogenesis of eosinophilic vs. non-eosinophilic chronic rhinosinusitis with nasal polyposis in Vietnamese – Genetics and Molecular Research (GMR)

  https://geneticsmr.com/2021/03/31/pathogenesis-of-eosinophilic-vs-non-eosinophilic-chronic-rhinosinusitis-with-nasal-polyposis-in-vietnamese/

  The study of the characteristics of non-eosinophilic and eosinophilic chronic polyposis rhinosinusitis (CRSwNP) is necessary to improve understanding of the pathophysiological mechanisms of this disease and determine the optimal treatment strategy. […] Eosinophilia plays an important role in the pathogenesis of this disease and significantly worsens the clinical picture. […] There are significant differences in the duration of the pathological manifestations, the presence of allergic rhinitis, bronchial asthma and the severity of polyps in patients with eosinophilic and non-eosinophilic CRSwNP.

• #59 Nasal steroid use and osteitis development in chronic rhinosinusitis with nasal polyps | The Egyptian Journal of Otolaryngology | Full Text

  https://ejo.springeropen.com/articles/10.1186/s43163-022-00328-5

  Osteitis and tissue remodeling are inflammatory processes associated with the severity of chronic rhinosinusitis with nasal polyps (CRSwNP). Nasal steroids are the mainly recommended therapeutics in the treatment of the disease, and besides their beneficial effects, they may worsen osteitis via osteopenia. […] Chronic inflammation of overlying sinus mucosa is accompanied by inflammatory changes on sinus bone, such as osteopathology, osteitis, neoosteogenesis, or osteopenia, and is also an established marker for severity and management of CRSwNP. […] Pathogenesis and epidemiology of osteitis in chronic rhinosinusitis (CRS) include clinical and biological such as previous sinus surgery, the severity of rhinosinusitis, the inflammatory pattern of rhinosinusitis, and biofilm formation. Current reviews suggest a process of neo-osteogenesis and bone remodeling, rather than bone infection or inflammation for osteitis in primary CRS.

• #60 Nasal steroid use and osteitis development in chronic rhinosinusitis with nasal polyps | The Egyptian Journal of Otolaryngology | Full Text

  https://ejo.springeropen.com/articles/10.1186/s43163-022-00328-5

  The mean GOS scores were detected significantly higher in patients with regular NSU, in this study, and there was no significant difference in GOS scores between patients without NSU and those with a total NSU for 13 months. But, patients with a NSU more than 3 months had a significant high GOS score than other two group. Consistent with the literature, there is a clear relationship between NSU and the development of osteitis. […] There is a tendency to develop osteitis with CRSwSP, and it is possible that this tendency may have made the bones of the paranasal sinuses vulnerable to the osteodegenerative effects of steroid use. So, it may be possible together to use longer-term nasal steroids due to the severity of osteitis (correlate with severity of CRSwNP) or to detect more severe osteitis due to nasal steroid use.

• #61 Nasal Polyps – Sound Health Services

  https://www.soundhealthservices.com/ent/nose/nasal-polyps/

  Sound Health Services is among the first in the United States to offer a non-surgical procedure for patients who suffer from repeat nasal polyps with SINUVA (mometasone furoate) Sinus Implant. SINUVA is proven to reduce polyps and nasal congestion and obstruction. […] SINUVA is a sinus implant that treats nasal polyps without surgery. During a routine office visit, a Sound Health physician will use topical and/or local anesthesia to numb the patients nose and sinuses. SINUVA is then placed in the sinus cavity through the nasal opening. […] Its innovative design provides a 2-in-1 approach: it is designed to open in the sinus cavity and release anti-inflammatory medicine to treat nasal polyps for up to 90 days.

• #62 Pathogenesis of nasal polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4422388/

  Importantly, defects in airway epithelial barrier function are associated with chronic airway diseases such as asthma. […] Together, these data suggest that eosinophils play many important roles in driving various aspects of CRSwNP disease and that research focused on targeting these cells specifically could be very beneficial. […] In summary, CRSwNP is a complex inflammatory condition, and many factors likely contribute to its pathogenesis. […] Defects in the basic functions of the airway epithelium coupled with elevated pro-inflammatory cytokines and chemokines likely combine to drive the chronic adaptive immune response found in NP.

• #63

  https://link.springer.com/article/10.1007/s12070-022-03247-2

  In the nasal polyps, a characteristic elevation of IgE is detected. […] Tissue stroma remodeling in the lamina propria occurs, mainly, by the formation of a net created by Fibrin, produced by fibroblasts, and FXIII-A factor, produced by macrophages. […] The most current trend, for the pathogenesis of nasal polyposis approach, is the epithelial immune barrier hypothesis which combines the intrinsic and extrinsic theories. […] According to this theory, a defective epithelial barrier and a dysfunctional repair system of damaged mucosa, render the sub-epithelial layer- lamina propria- more vulnerable to invasion by pathogens. […] Overall, the idiopathic nasal polyposis in western populations does not seem to have a typical allergic background. […] Several theories are explaining the etiology that skews the immune response towards Th-2. […] Finally, the most current theory that combines all the other pathogenetic mechanisms is that of the epithelial immune barrier dysfunction.

• #64 Biologics for Chronic Rhinosinusitis with Nasal Polyps | AAO-HNS Bulletin

  https://bulletin.entnet.org/clinical-patient-care/article/22881642/biologics-for-chronic-rhinosinusitis-with-nasal-polyps

  Biologics are monoclonal antibodies developed through recombinant technology. They act by targeting a specific protein considered germane in the pathogenesis of a disease. Three biologics targeting type 2 inflammation in CRSwNP have recently been approved by the U.S. Food and Drugs Administration (FDA): dupilumab, mepolizumab, and omalizumab. […] Table 1 summarizes the mechanism of action for each of the approved biologics, while Figure 1 also depicts where these biologics target nasal polyp pathogenesis. […] Dupilumab was first approved for noncontrolled moderate to severe atopic dermatitis. […] Dupilumab, mepolizumab, and omalizumab were all successful in demonstrating increased efficacy in the primary end point of decreasing the nasal polyp size. […] Three biologics targeting type 2 inflammation have recently been approved by the FDA for nasal polyps: dupilumab, mepolizumab, and omalizumab. These appear to reduce nasal polyp size and positively impact sinonasal symptoms and quality of life with varying efficacy. Many questions on the use of biologics for nasal polyps currently remain unanswered regarding the length of treatment, who benefits most, and whether biologics should be used with, without, before, or after surgery.

• #65 Frontiers | Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1139240/full

  The dysregulation of 1α-hydroxylase and vitamin D in the sinuses in CRS has been reported previously. […] The phenomenon of EMT has been observed in patients with CRS and there is also evidence that it affects patients with CRSwNP. […] Canonical Wnt signaling has been demonstrated to be activated in nasal polyps, triggering epithelial disorders such as compromised adherens junctions and reduced ciliogenesis, which can in turn stimulate cytokine release. […] Epithelial disorder is pivotal in the etiology or pathogenesis of CRS; epithelial barrier disruption and MCC dysfunction constitute the fundamental pathogenesis of CRS. […] Overall, considering the importance of sinonasal epithelium-mediated immunity disorders for CRS pathogenesis, vigorous efforts should be applied to the development of novel biological agents that can antagonize the actions of inflammatory bioactive components produced by the epithelium, maintain the immune balance of the nasal mucosa, alleviate local inflammation, and reduce nasal polyp formation.

• #66 Pathogenesis of nasal polyposis

  https://www.periodicos.capes.gov.br/index.php/acervo/buscador.html?task=detalhes&id=W1972104377

  Pathogenesis of nasal polyposis […] Chronic rhinosinusitis with nasal polyps (CRS w NP) is a complex inflammatory condition that affects a large proportion of the population worldwide and is associated with high cost of management and significant morbidity. Yet, there is a lack of population-based epidemiologic studies using current definitions of CRS w NP, and the mechanisms that drive pathogenesis in this disease remain unclear. In this review, we summarize the current evidence for the plethora of factors that likely contribute to CRS w NP pathogenesis. Defects in the innate function of the airway epithelial barrier, including diminished expression of antimicrobial products and loss of barrier integrity, combined with colonization by fungi and bacteria likely play a critical role in the development of chronic inflammation in CRS w NP. This chronic inflammation is characterized by elevated expression of many key inflammatory cytokines and chemokines, including IL 5, thymic stromal lymphopoietin and CCL 11, that help to initiate and perpetuate this chronic inflammatory response. Together, these factors likely combine to drive the influx of a variety of immune cells, including eosinophils, mast cells, group 2 innate lymphoid cells and lymphocytes, which participate in the chronic inflammatory response within the nasal polyps. Importantly, however, future studies are needed to demonstrate the necessity and sufficiency of these potential drivers of disease in CRS w NP. […] Given the high prevalence, costs and morbidity, there is a great need for continued research into CRS that could facilitate the development of novel therapeutic strategies to improve treatment for patients who suffer from this disease.

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