Hyperresponsiveness unlinked to ASM Contraction

Despite methacholine-induced hyperresponsiveness being present in vivo, ASM contraction in excised tracheas and precision cut lung slices (PCLS) showed no corresponding increase, suggesting that lung tissue compliance—not ASM hypercontractility—is a primary driver. Moreover, ex vivo data in PCLS demonstrated a decrease in sensitivity to methacholine in the asthma model of the mouse, for both species tested.

Central to the ex vivo discoveries was the physioLens, an innovative imaging platform designed to measure airway constriction in PCLS. By enabling high-throughput and precise analysis of ASM responses, the physioLens facilitated a deep understanding of how lung tissue mechanics influence methacholine-induced changes in respiratory function. The platform’s ability to capture dynamic airway behavior was instrumental in isolating the role of ASM from overall tissue mechanics.

The results revealed a striking link between lung tissue compliance and methacholine responsiveness. BALB/c mice, which have more compliant lung tissue, demonstrated a heightened response to methacholine. Conversely, the stiffer lungs of C57BL/6 mice mitigated their responsiveness. Notably, the hyperresponsiveness observed in vivo was not matched by increased ASM contractility in ex vivo tests, underscoring the influence of lung mechanics over smooth muscle behavior.

Implications for Asthma Research

This study underscores the complexity of asthma and the importance of considering lung tissue properties alongside ASM behavior. While BALB/c mice’s lung compliance appears to model certain extreme phenotypes of human asthma, such as asthma-COPD overlap syndromes, their relevance to typical asthma cases warrants further exploration. Additionally, the findings challenge conventional assumptions, reinforcing the idea that factors beyond ASM hypercontractility play critical roles in hyperresponsiveness.