The Identification of Airway Squamous Metaplasia Inhibitors: Modulating Cell Fate as a Therapeutic Strategy

Abstract

In humans, the conducting airway consists of a pseudostratified epithelium with three main cell types: secretory, ciliated and basal cells. Airway basal cells act as multipotent stem cells, which proliferate and differentiate into luminal secretory cells (goblet and club cells) as well as ciliated cell. The proper balance between basal cell proliferation and differentiation into the appropriate numbers of types of specialized cell of the epithelium is essential for defending against airborne pathogens and other insults as well as for tissue homeostasis. Pathological remodeling of these cell types occurs in conditions such as chronic obstructive pulmonary disease (COPD). Epithelial phenotypes can range from basal to goblet cell hyperplasia and squamous metaplasia, resulting in impaired mucociliary clearance, an increase in bacterially-colonized airways, and pulmonary exacerbations. Here, I describe a 384-well, three‐dimensional (3‐D) organoid squamous metaplasia model used to screen for modulators of airway squamous metaplasia (ASM), and the identification of a small molecule inhibitor of ASM, ASMi-1 (airway squamous metaplasia inhibitor-1). Real-time quantitative RT-PCR and immunohistochemistry were used to examine markers of normal differentiated cells types and squamous epithelial markers. ASMi-1 resulted in the restoration of the mucociliary and squamous markers. Front line therapies for COPD focus on symptomatic management and not by treating the underlying cause of the disease. Addressing airway remodeling as a strategy to restore homeostasis in an airway that has undergone squamous metaplasia may result in sustained, improved lung function. This work may provide a rationale for development of a new class of therapies to treat pulmonary disorders such as COPD.