Abstract
Chronic lung diseases (CLDs) represent a set of disorders characterized by the progressive loss of proper lung function. Among severe CLDs, the incidence of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) has grown over the last decades, mainly in the elderly population. Several studies have highlighted an increased expression of senescence-related markers in the resident progenitor cells in COPD and IPF, possibly undermining epithelial integrity and contributing to the progression and the aggravation of both diseases. Recently, the chronic activation of the canonical Wnt/β-catenin pathway was shown to induce cellular senescence. Here, we investigated the localization and the expression of leucin-rich repeat-containing G-protein-coupled receptor 6 (LGR6), a protein that activates and potentiates the canonical Wnt signalling. Through immunohistochemical analyses, we identified a lesion-associated rise in LGR6 levels in abnormal lung epithelial progenitors in COPD and IPF when compared to histologically normal tissues. Moreover, in areas of aberrant regeneration, chronic damage and fibrosis, LGR6-expressing epithelial progenitors displayed a major increase in the expression of senescence-associated markers. Our study suggests the involvement of LGR6 in the chronic activation of the Wnt/β-catenin pathway, mediating the impairment and exhaustion of epithelial progenitors in COPD and IPF.
Highlights
Aging is one of the main risk factors for developing chronic life-threatening conditions [1]
Our understanding of pivotal mechanisms involved in chronic lung diseases (CLDs) has improved in recent decades, not to the complete elucidation of the complex machinery contributing to chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) development and exacerbation [7,8,43,44,45,46,47]
Whilst in patients with IPF, the involvement of Wnt/β-catenin signalling has been widely investigated in recent decades [15,16,17], in COPD the activation of canonical Wnt pathway is still debated and its upregulation may be lesion specific [12,18,19]
Summary
Aging is one of the main risk factors for developing chronic life-threatening conditions [1]. Proliferation of resident bronchiolar and alveolar progenitors is critical for tissue regeneration in the light of re-establishing tissue homeostasis and maintaining correct lung functionalities [9]. As surfactant protein-C (SPC+), ATII cells are the main alveolar progenitors and can differentiate into ATI cells and regenerate the distal lung epithelium [9]. The role of canonical Wnt signalling as a critical regulator for balancing stem cell proliferation and differentiation and as an inhibitor of apoptosis has been established for several human tissues and related diseases [11]. Despite the fact that recent studies have provided new insights about the activation of the canonical Wnt pathway in IPF [15,16,17], the involvement of Wnt/β-catenin signalling in COPD is less clear. While previous findings suggested a shift from canonical to non-canonical Wnt pathway activation in emphysema [18], recent investigations showed that the Wnt/β-catenin pathway may be upregulated in the airway epithelium of patients with COPD [12,19]
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