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Chronic Rhinosinusitis with Nasal Polyps: A "Module-First" Review of Murine Models and Chemical Interventions
Yunfei Gao1,2, Gengluan Liu2,3, Caiyan An4
1Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Abstract:
Chronic rhinosinusitis with nasal polyps (CRSwNP) comprises multiple molecular endotypes that only partly align with the clinical phenotype, which complicates target selection and interpretation of treatment effects. Human omics and biomarker studies define candidate pathways, but causal attribution of specific nodes to lesion formation and remodeling requires perturbable in vivo systems. Here, we present a "module-first" framework that links murine induction paradigms to epithelial-immune-stromal circuits and to a minimal, module-matched endpoint set for reproducible causal inference. We summarize commonly used CRSwNP-like protocols (allergen/protease ± SEB, aeroallergen + SEB, innate trigger-enriched paradigms, and modifier layers), emphasize operational pathology terminology ("polyp-like lesion" versus "true polyp"), and propose a uniform causal template for validated pathway modules (alarmins/IL-33-NF-κB, type 2/ILC2-eosinophil, IL-17A/neutrophil, Wnt/EMT remodeling, and JAK/STAT kinase convergence). Finally, we organize chemical and molecular interventions by leverage point and propose an ARRIVE-aligned Minimum Reporting Set to standardize model anchoring, target engagement, and cross-study comparability. This module-first roadmap is intended to accelerate mechanism-linked discovery and preclinical validation of tractable drug targets in CRSwNP. Importantly, this module-first roadmap is intended as a heuristic organizing principle rather than an exhaustive taxonomy, because pathway modules can overlap and shift dynamically across time and tissue compartments in vivo.
Insights
This study introduces a "module-first" framework to understand chronic rhinosinusitis with nasal polyps (CRSwNP) by linking mouse models to biological pathways. This approach aims to accelerate the discovery of new drug targets for CRSwNP.
Area of Science:
- Immunology
- Pathology
- Translational Medicine
Background:
- Chronic rhinosinusitis with nasal polyps (CRSwNP) has diverse molecular subtypes not fully matching clinical presentations, hindering targeted treatments.
- Current human studies identify pathways but lack in vivo systems for causal links to disease mechanisms.
- Developing perturbable in vivo models is crucial for attributing specific molecular nodes to CRSwNP lesion formation and tissue remodeling.
Purpose of the Study:
- To present a "module-first" framework connecting murine models to epithelial-immune-stromal circuits for CRSwNP research.
- To establish a minimal, module-matched endpoint set for reproducible causal inference in CRSwNP pathogenesis.
- To propose a standardized roadmap for accelerating mechanism-linked discovery and preclinical validation of drug targets in CRSwNP.
Main Methods:
- Summarized common CRSwNP-like induction protocols in murine models (e.g., allergen, protease, SEB, innate triggers).
- Defined operational pathology terms like "polyp-like lesion" vs. "true polyp" for clarity.
- Proposed a causal template for key pathway modules (e.g., alarmins/IL-33-NF-κB, type 2/ILC2-eosinophil, IL-17A/neutrophil, Wnt/EMT, JAK/STAT).
Main Results:
- Organized chemical and molecular interventions based on their leverage points within the proposed pathway modules.
- Recommended an ARRIVE-aligned Minimum Reporting Set to standardize model anchoring and target engagement.
- Highlighted the dynamic and overlapping nature of pathway modules in vivo.
Conclusions:
- The module-first framework provides a heuristic for organizing CRSwNP research and standardizing preclinical validation.
- This approach aims to accelerate the identification and validation of tractable drug targets for CRSwNP.
- Improved standardization and causal inference are key to advancing CRSwNP treatment strategies.
