Applications of PCLS in COPD Research

Airway Contractility and Hyperresponsiveness

Altered airway smooth muscle contractility and small airway hyperresponsiveness are hallmark features of COPD. Studies utilizing PCLS have provided valuable insights into these mechanisms:

• Altered Contractility and Stiffness: Su et al. (2013) and An et al. (2012) highlighted how impaired relaxation and altered contractility contribute to COPD pathogenesis.
• Modeling Small Airway Hyperresponsiveness: Human and guinea pig PCLS models (Maarsingh et al., 2019; Van Der Koog, 2023) have demonstrated airway hyperresponsiveness in COPD. Elastase-induced parenchymal disruption in murine PCLS (Van Dijk et al., 2017) offers an animal model for studying COPD progression.
• Cigarette Smoke Exposure: PCLS exposed to cigarette smoke condensate mimic COPD-relevant outcomes such as airway and vessel contractility in rodent, rhesus monkey, and human models (Moreno, 2006; Wright, 2008). Additionally, several studies (Danov et al 2020, Obernolte et al 2019) have used the expoCube to deliver cigarette smoke to PCLS to suppress antiviral cytokine responses and disrupt epithelial barrier functions. 

Calcium Imaging

Calcium signaling plays a pivotal role in airway smooth muscle contraction and inflammatory responses in COPD. PCLS enable real-time imaging of calcium flux, providing insights into pathophysiological processes and potential therapeutic targets.

Histological and Morphometric Analyses

PCLS preserve the structural integrity of lung tissue, enabling detailed histological evaluations:

• Airway and Alveolar Pathology: Studies like Kim et al. (2023) assess airway narrowing, alveolar destruction, and mucus hypersecretion in COPD-derived PCLS.
• Drug Discovery: Uhl et al. (2015) and Skronska-Wasek (2017) demonstrated the potential of pharmacological activation of Wnt/β-catenin signaling to initiate epithelial repair in COPD-derived PCLS.
• 3D Reconstruction: Advanced imaging techniques, such as those used by Alsafadi (2020), allow visualization of collagen I and E-cadherin staining in healthy and COPD explants.
• Ciliary Function: Impaired cilia beating frequency is a characteristic of COPD that contributes to poor mucociliary clearance. PCLS models have shown:
  • Dysfunctional Cilia in COPD: Studies like Thomas (2021) and Ancel (2021) highlighted the reduced ciliary beat frequency in COPD patients.
  • Infectious Disease Models: Li et al. (2024) explored cilia dysfunction in PCLS exposed to infectious agents.

Immune Modulation

The immune response in COPD is a critical area of study. Using PCLS, researchers have:

• Investigated the role of Toll-like receptor 3 activation in cytokine secretion (Cooper, 2009).
• Studied inflammatory pathways relevant to COPD exacerbations.

Metabolic studies

PCLS provide a platform to examine lung metabolism in COPD. Yilmaz et al. (2019) assessed phase I and phase II enzyme activities in rat and human PCLS, highlighting metabolic alterations in COPD.

Mucus Production and Secretion

PCLS models mimic the expression and secretion of mucins (e.g., MUC5B, MUC5AC) seen in COPD airways. Hoang, et al (2022) demonstrated how human PCLS can serve as a platform to study mucus hypersecretion and its regulation.

Conclusion

The versatility of PCLS makes them an indispensable tool for preclinical COPD research. Their applications extend from disease modeling to therapeutic screening, bridging gaps in translational research. Key opportunities include:

• Expanding the use of human-derived PCLS to identify novel biomarkers and validate therapies.
• Enhancing 3D imaging techniques for better visualization of disease pathology.
• Integrating PCLS studies with omics approaches to uncover molecular mechanisms.