Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults

Abstract

Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.

Keywords: granulomatosis with polyangiitis; relapsing polychondritis; subglottic stenosis; tracheal stenosis; tracheostomy; web-like stenosis.

Figure 1

Immunological response and tracheal scarring in iatrogenic and idiopathic tracheal; Panel (A): iatrogenic tracheal stenosis is sustained by lymphocyte TH2 response that promotes fibroblasts activation and myofibroblasts differentiation. Furthermore, TH2 response through IL-13 induction promotes alternative polarization of macrophages to a profibrotic M2 phenotype, which in turn acts by inducing fibroblast activation via TGF-Β1 and arginase-1 expression. See text for more details; Panel (B): idiopathic subglottic stenosis seems related to γδT cell activation as a consequence of disrupted tracheal microbiota. γδT cells induce activation of the IL-17A/IL23 inflammatory axis, which acts in synergy with TGF-Β1 in promoting myofibroblasts differentiation and scarring development.

Figure 2

Physiological changes in LTS stenosis; Panel (A): In normal tracheal section (A1), physiological airways pressure (P1) is associated with normal airflow velocity (V1). In patients suffering from LTS, a hyperactivation of the respiratory drive occurs to overcome airways resistance at the site of stenosis. The inspiratory effort determines high inspiratory flow and elevated pleural pressure swing, as illustrated by ΔPes. At the site of stenosis (A2), according to the Venturi effect, the increase in airflow velocity at stenosis level (V₂) is associated with a reduction in airway pressure (P₂) resulting in a pressure drop, which acts on the tracheal wall. These physiological changes may exert unphysiological stress and strain on the tracheal mucosa at the site of stenosis during breathing in patients with LTS; Panel (B): Stress–strain relationship in healthy trachea and in tracheomalacia. During breathing, tracheal wall is subject to mild mechanical stimuli, which results in a negligible tracheal deformation (strain < 10%). In patients with severe LTS (reduction in patency > 70%) pressure drop at the site of stenosis increases mechanical stimuli on the tracheal wall resulting in unphysiological stress–strain. The consequent changes of mechanical microenvironment may activate mechanotransduction pathways in local fibroblasts, promoting myofibroblast differentiation and collagen deposition; V₁: airflow velocity before stricture, V₂: airflow velocity at stenosis site, P₁: pressure in the airway before stricture, P₂: pressure in the airway at stenosis site, A₁: area of healthy trachea, A₂: area at stenosis sit.