Pulmonary

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by progressive and irreversible airflow limitation, chronic airway inflammation, lung function decline, and breathing problems (1, 2). Dysregulation of signaling pathways involved in lung tissue development and regeneration, such as Wnt, Notch, and Hedgehog, influence the pathophysiology of this disease (3). 

Chronic obstructive pulmonary disease (COPD) is a common lung disease and the third leading cause of death worldwide (4). It happens due to long-term exposure to harmful particles or gases, often tobacco smoke. Other risk factors of COPD include abnormal lung development and faster aging (8). Importantly, genetic susceptibility may also play a role in the development of this disease. Researchers have identified a few genes associated with an increased risk of COPD, including FAM13A, HHIP, MTCL1, TGFB2, CYP2A6, EEFSEC, and SFTPD (5, 6, 7).

Pathological changes in the lungs that occur with the disease may result in symptoms such as shortness of breath, cough, wheezing, sputum production, and chest tightness (9). COPD may also contribute to other health issues, including hypertension, heart disease, obstructive sleep apnea, anxiety, and depression (10).

COPD is a complex inflammatory disease that affects the airways, lung parenchyma, and pulmonary blood vessels, eventually leading to respiratory failure (9, 11). The two most common types of COPD are emphysema and chronic bronchitis (12). The pathogenesis of this disease isn’t completely understood (13, 2). It is thought to involve oxidative stress, inflammation, protease-antiprotease imbalance, apoptosis-proliferation imbalance, metabolic reprogramming, reduced immunity, autophagy, and mitochondrial dysfunction (13).

Aberrations in signaling pathways involved in various developmental processes may trigger the initiation and progression of COPD. Identified signaling pathways include WNT, HIF, and NF-κB. These pathways are valuable targets for drug development and may help improve treatment approaches for this highly complex disease.

WNT signaling pathway

The WNT signaling pathway is an evolutionarily conserved signaling pathway involved in developmental processes, including cell fate determination, migration, proliferation, apoptosis, and migration (14). Notably, it’s involved in lung development, homeostasis, repair, and regeneration. When dysregulated, this pathway contributes to the pathogenesis of COPD and other lung diseases (15).  

WNT is an extracellularly secreted glycoprotein whose signaling consists of Wnt genes and receptors. WNT pathway may be canonical (β-catenin-dependent) or noncanonical (B-catenin-independent) (14). It has been shown that repeated exposure to cigarette smoke causes the dysregulation of canonical and noncanonical Wnt signaling pathways, which then contribute to pathological changes associated with the disease, such as airway remodeling and inflammation, protease-antiprotease imbalance, mucus hyperproduction, and metabolism reprograming (13, 8,).

Since the WNT pathway has a role in COPD pathogenesis, it could be a target for novel treatments.

NF-κB signaling pathway

The abnormal activation of the NF-κB signaling pathway may also trigger the onset and progression of COPD.

NF-κB is a family of inducible transcription factors, including p50, p52, p65, c-RelA, and RelB (16). It regulates genes involved in biological processes, including cell survival, differentiation, proliferation, death, inflammation, and immune response (17). Aberrant NF-κB activation associated with COPD is induced by inflammatory mediators, including IL-1β and TNF-α or toll-like receptor (TLR) activation caused by bacterial or viral flare-ups (18, 16).

Chronic lung inflammation is a principal characteristic of COPD that involves inflammatory mediators, including cytokines, chemokines, and cell adhesion molecules (CAMs) (19). NF-κB regulates the expression of these inflammatory mediators, making it pivotal in COPD-induced inflammation (18). Increased NF-κB activity has been found in the airways of patients with stable and exacerbated COPD (20). 

With its central role in the pathogenesis of COPD, researchers suggest the potential of developing drugs that target the NF-κB signaling pathway to better treat COPD. However, the potential to create drugs inhibiting this pathway is limited due to its crucial role in tissue homeostasis and immune function (16). For example, inhibiting NF-κB to manage COPD may impede anti-viral responses (20).

Notch signaling pathway

The Notch signaling pathway is extensively involved in lung development, homeostasis, repair, and regeneration. Hence, its dysregulation is relevant to lung diseases such as COPD (21).

Notch is a highly conserved cell-cell communication pathway consisting of Notch receptors (Notch1-4), Delta-like ligands (Dll)-1,-3, and -4, and Serrate-like ligands (Jagged-1 and -2). It is vital to cell fate determination, proliferation, and differentiation. It also supports stem cell quiescence and identity (22).

Evidence suggests that Notch signaling pathway components are altered in the lungs of smokers with and without COPD compared to non-smokers (23). For instance, Notch pathway genes, including Dll1, Notch3, Hes5, Hey1, and Hey2, have been shown to be downregulated in COPD (24). This dysregulation is associated with pathological events in COPD, including mucosal hyperplasia and endothelial cell apoptosis (21).

Research suggests that targeting Notch signaling activity as a novel COPD treatment is promising (21).

HIF signaling pathway

Hypoxia-inducible factors (HIF) is a family of heterodimeric transcription factors that includes HIFα subunits, HIF-1α, HIF-2α, and HIF-3α, and HIF-1β (25). HIF-1 is widely recognized as a “master regulator of oxygen homeostasis” (26).

Prolonged exposure to cigarette smoke results in tissue hypoxia, a state of inadequate oxygen supply (27). Hypoxia leads to the activation of HIF signaling, which regulates the cellular response to hypoxia (28, 29).

Studies have found that HIF-1α and its downstream target genes, including VEGF and VEGFR2, are overexpressed in the lungs of individuals with COPD relative to healthy individuals (30).  Overexpressed HIF-1α upregulates inflammatory markers by activating the EGFR/PI3K/AKT pathway. The lung inflammation-induced EGFR/PI3K/AKT pathway leads to upregulating HIF-1α, creating a positive feedback loop promoting COPD progression. HIF-1α signaling also contributes to the development of lung cancer related to COPD (31).

Researchers suggest that inhibiting HIF-1α expression in COPD may be beneficial in managing COPD severity and disrupting the progression from COPD to lung cancer (30).

Hedgehog signaling

The Hedgehog pathway is a critical developmental signaling pathway involved in lung development and repair. Chronic smoking results in the abnormal activation of this pathway in COPD (32).

By regulating pro-inflammatory cytokines, including IL-6 and IL-8, and triggering abnormal alveolar and bronchial epithelial cell apoptosis, Hedgehog signaling can promote airway inflammation, contributing to COPD onset and progression (32).

Hedgehog-interacting protein (HIP), a negative regulator of Hedgehog signaling, may be protective in COPD. However, it has been shown to be underexpressed in the lung tissues of 32% of patients with COPD compared with smokers without airflow limitation (32).

It’s been proposed that targeting Hedgehog signaling may be a valuable approach to treating patients with smoking-related COPD (32).

Interleukin-17 (IL-17)

Interleukin-17 (IL-17) is a proinflammatory cytokine primarily produced by T helper 17 (Th17) cells. Studies suggest that IL-17 levels are elevated in people with COPD than healthy controls. IL-17 signaling significantly contributes to pathological events associated with COPD, such as neutrophil recruitment and inflammation, smooth muscle proliferation, airway remodeling, worsening airway inflammation, and airway damage (33, 34).

Additionally, IL-17 facilitates IL-8 expression and the upregulation of other pro-inflammatory cytokines in COPD. IL-8 is involved in COPD pathogenesis as it promotes the accumulation of neutrophils in the bronchial epithelium and airway inflammation. It also contributes to steroid resistance, a limiting factor in treatment effectiveness (34).

Researchers suggest that drugs that inhibit IL-17 and other proinflammatory mediators of COPD with as few side effects, such as Bufei Yishen formula (BYF) and Curcumin, are promising for treating COPD, particularly acute exacerbation of COPD (34, 35).

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