Airway smooth muscle in contractility and remodeling of asthma: potential drug target mechanisms

ABSTRACT

Introduction

Asthma is characterized by enhanced airway contractility and remodeling where airway smooth muscle (ASM) plays a key role, modulated by inflammation. Understanding the mechanisms by which ASM contributes to these features of asthma is essential for the development of novel asthma therapies.

Areas covered

Inflammation in asthma contributes to a multitude of changes within ASM including enhanced airway contractility, proliferation, and fibrosis. Altered intracellular calcium ([Ca²⁺]_i) regulation or Ca²⁺ sensitization contributes to airway hyperreactivity. Increased airway wall thickness from ASM proliferation and fibrosis contributes to structural changes seen with asthma.

Expert opinion

ASM plays a significant role in multiple features of asthma. Increased ASM contractility contributes to hyperresponsiveness, while altered ASM proliferation and extracellular matrix production promote airway remodeling both influenced by inflammation of asthma and conversely even influencing the local inflammatory milieu. While standard therapies such as corticosteroids or biologics target inflammation, cytokines, or their receptors to alleviate asthma symptoms, these approaches do not address the underlying contribution of ASM to hyperresponsiveness and particularly remodeling. Therefore, novel therapies for asthma need to target abnormal contractility mechanisms in ASM and/or the contribution of ASM to remodeling, particularly in asthmatics resistant to current therapies.

KEYWORDS:

• Lung
• airway
• airway smooth muscle
• calcium
• airway hyperreactivity
• proliferation
• fibrosis
• drug targets

Article highlights

• Despite therapeutic advances, asthma significantly impacts patients’ lives and overall healthcare

• Increased insight into mechanisms contributing to asthma has broadened therapeutic options and allowed for more goal-oriented therapies

• Therapeutic advances of drug delivery have broadened the potential targets of drug delivery and allowed for improved combined therapeutics

• These advances have improved treatment options for asthmatics but also demonstrated future needs

This box summarizes key points contained in the article.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors contributed equally to this review.

Additional information

Funding

This review was funded by the Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, Rochester, MN, and by NIH grants R01 HL142061 (CM Pabelick and YS P) and R01 HL088029 (YS P).