Work

Impairment of pulmonary microvascular endothelial cells: The ground for COPD?

Year: 2024

Type: article

Abstract: To the Editor: Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by abnormalities in the airways (bronchitis and bronchiolitis) and alveoli (emphysema), as well as pulmonary inflammation, leading to persistent and progressive airflow obstruction.[1] Pulmonary microvascular endothelial cells (PMECs), the main component of pulmonary microvasculature, accounts for about 23% of the human lung cells. PMECs play a pivotal role in the progression of COPD by maintaining lung homeostasis and being involved in various pathogenic processes. Firstly, PMECs are essential for the integrity of the pulmonary blood–gas barrier, facilitating efficient gas exchange. Damage to the PMECs disrupts this barrier, leading to increased permeability, edema, and impaired gas exchange, which are hallmark features of COPD. Secondly, PMECs regulate inflammatory responses by releasing cytokines and chemokines that attract immune cells. Dysfunctional PMECs in COPD contribute to chronic inflammation and subsequent lung tissue damage, exacerbating disease progression. Additionally, PMECs are crucial in pulmonary vascular remodeling, where endothelial dysfunction and apoptosis lead to structural changes, increased pulmonary vascular resistance, and pulmonary hypertension. PMECs are also highly susceptible to oxidative stress, which induces reactive oxygen species production and apoptosis, disrupting vascular integrity and promoting emphysema. Lastly, PMECs possess repair and regeneration capabilities, but chronic exposure to damaging stimuli in COPD impairs these processes, highlighting the importance of maintaining PMEC function to mitigate disease progress. Therefore, impairment of PMECs leads to vascular barrier defects, alveolar damage, and pulmonary inflammation, which are preceding the decline in lung function, thereby indicating that PMEC injury is pivotal in COPD development and progression. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 guidelines emphasize the importance of addressing early-stage COPD, including patients with preserved ratio impaired spirometry (PRISm),[2] who exhibit early pulmonary abnormalities. This underscores the potential significance of intervening in PMEC injury during the early stages of COPD for effective disease management. This review summarized the current understanding of endothelial injury in the occurrence and development of COPD, analyzed the status and limitations of vascular protective drugs in COPD treatment, and proposed the direction of COPD treatment based on microvascular endothelial protection. Factors causing PMEC impairment in COPD: PMECs are crucial in maintaining lung homeostasis, and their impairment is a key factor in the progression of COPD. Several environmental and pathogenic factors contribute to PMEC impairment, including cigarette smoking (CS), infections, household biomass smoke, outdoor air pollution, and occupational exposure to dust and fumes. These risk factors can affect endothelial function and especially cause structural and functional damage to the PMECs. CS is a major factor impairing the PMECs in COPD by inducing oxidative stress, triggering inflammatory responses, causing endothelial dysfunction, promoting apoptosis, and hindering repair mechanisms. These processes contribute to the progression of COPD by disrupting the pulmonary microvascular barrier, leading to increased permeability, chronic inflammation, and tissue damage. Endothelial injury in early COPD development: PMEC dysfunction is an early feature of COPD. Lung microvascular blood flow (LMBF) decreases occur in early COPD, persist throughout the course of the disease, and correlate positively with emphysema severity.[3] Endothelial dysfunction, evidenced by brachial artery flow-mediated dilation assessments, occurs in early stages and correlates with COPD severity.[4] Increased levels of cluster of differentiation 31 positive (CD31+) endothelial cell microparticles in COPD patients, negatively correlated with LMBF,[5] exacerbate endothelial dysfunction and cell apoptosis. Pulmonary imaging studies have shown that changes in pulmonary ventilation–exchange functions occur before noticeable lung function decline.[6] Animal studies indicated that PMEC damage and changes in vascular mediators precede emphysema in CS-induced COPD models.[7] Moreover, single-cell RNA sequencing (scRNA-seq) identified an inflamed phenotype of capillary endothelial cells, likely increased C-X-C Motif Chemokine Ligand 12 (CXCL12) signaling from alveolar capillary stem cells, in the lungs of mice exposed to CS for 10 weeks.[8] These findings suggest that structural and functional disturbances of PMECs lead to microcirculation and microenvironment changes in the alveoli. Such disturbances can serve as early diagnostic markers and therapeutic intervention targets for COPD, aligning with the GOLD 2023 guidelines that emphasize early detection and management of pulmonary abnormalities associated with COPD.[2] Expanded research on endothelial dysfunction and COPD: Several pre-clinical studies have demonstrated the potential benefits of drugs targeting PMECs in COPD. For instance, pitavastatin maintains endothelial barrier integrity by preventing the downregulation of tight junction proteins induced by CS exposure. Atorvastatin has been shown to improve lung function and the lung blood–air barrier in COPD models. Pioglitazone and irbesartan protect endothelial cells by upregulating nitric oxide levels, thereby enhancing endothelial function. Moreover, inhibiting inducible nitric oxide synthase (iNOS) effectively prevents CS-induced pulmonary vessel and alveolar damage. Blocking the leucine-rich alpha-2-glycoprotein-1 (Lrg1) pathway through intravenous delivery of healthy PMECs or deleting Lrg1 from endothelial cells has shown potential in treating alveolar destruction in a mouse model of COPD/emphysema.[7] Angiotensin receptor blockers (ARBs) have been shown to improve lung histopathology in CS-induced mouse emphysema models.[9] Recent research highlights the critical role of endothelial cells in COPD pathogenesis. The loss of endothelial markers correlates with pulmonary function decline and increased emphysema severity, suggesting that endothelial apoptosis and dysfunction significantly contribute to COPD progression. Endothelial-derived angiocrine factor signaling, through pathways like vascular endothelial growth factor A (VEGF-A), fibroblast growth factors (FGF), matrix metalloproteinase-14 (MMP14), and bone morphogenetic protein 4 (BMP4), is essential for alveolar epithelial progenitor cell differentiation, proliferation, and repair. CS and hypoxia lead to pulmonary artery vasoconstriction and vascular remodeling, as well as dysfunctional pulmonary artery endothelial cells (PAECs) that contributing to intimal layer thickening and hyper-proliferative pulmonary artery smooth muscle cells (PASMCs), thereby reducing the vascular lumen and exacerbating pulmonary hypertension associated with COPD.[10] These studies highlight the importance of targeting endothelial dysfunction in COPD treatment. Understanding the mechanisms underlying endothelial injury and developing targeted therapies can improve outcomes for COPD patients. Clinical implications and limitations: Despite promising pre-clinical results, the endothelial protective properties of several first-line COPD drugs remain under investigation. Inhaled corticosteroids like budesonide and the combination of indacaterol/glycopyrronium have shown potential in reducing PMEC membrane permeability, protecting PMEC function, and improving pulmonary microvascular blood flow in COPD patients.[3] Vasoactive drugs such as angiotensin-converting enzyme inhibitors (ACEIs), ARBs, calcium antagonists, phosphodiesterase-5 (PDE-5) inhibitors, prostacyclin and its derivatives have demonstrated dual cardiorespiratory protective properties. These benefits include preventing the rapid decline of pulmonary function, slowing the progression of emphysema, and reducing the exacerbation rate, pneumonia, and mortality in COPD patients. However, the effectiveness of these drugs remains controversial as the results of cohort studies have not been consistently reproduced in randomized controlled trials (RCTs). Specifically, no significant improvement in pulmonary function has been observed in COPD patients using vasoactive drugs in RCTs. Several factors may explain this discrepancy. First, many vasoactive drugs do not specifically target microvascular injury, particularly pulmonary microvascular injury. For example, ACEIs improve endothelial function by reducing angiotensin (Ang) and endothelin-1 (ET-1) synthesized by endothelial cells, restoring nitric oxide bioavailability, and preventing Ang II-induced vasoconstriction.[11] Pitavastatin activates liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling, which inhibits interferon-gamma (IFN-γ)-induced hyperpermeability of human PMECs, thereby preventing cigarette smoke-induced endothelial barrier permeability.[11] However, these mechanisms are not specific to the microvascular endothelium. Second, the insufficient efficacy of vasoactive drugs in COPD treatment may be due to a mismatched intervention time window. Pulmonary microvascular endothelial injury occurs early in COPD development and persists throughout the disease. However, COPD is typically diagnosed after significant lung function decline, representing a post-injury stage for endothelial cells. This delayed diagnosis and intervention may reduce the effectiveness of endothelial-targeted therapies. Lastly, due to the heterogeneity of PMECs, therapies targeting endothelial dysfunction require further refinement. Differences in cell populations and responses to injury and treatment across the pulmonary microvascular endothelium complicate the development of universally effective treatments. While the clinical benefits of endothelial protection-based treatments for COPD have not been fully established, the potential for such strategies to provide effective intervention remains promising. Continued research and targeted drug development focusing on endothelial protection are warranted. Additionally, understanding the complex interplay among endothelial dysfunction, pulmonary vascular remodeling, and COPD pathogenesis will be crucial for developing new therapeutic approaches. Funding This work was supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No. ZYYCXTD-D-202206), the Key Project of National Natural Science Foundation of China (No. 82130123), the Natural Science Foundation of Hebei Province (Nos. H2023106039 and H2021106032), the S&T Program of Hebei (Nos. E2020100001 and 23372508D), the National Natural Science Foundation for Youth Project (No. 82205319), and the Scientific Research Project of Hebei Provincial Administration of Traditional Chinese Medicine (No. 2024401). Conflicts of interest None.

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003280