Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil VSports app下载. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure V体育官网. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. .

. 2018 Jan-Mar;8(1):2045894018758528.
doi: 10.1177/2045894018758528.

COPD as an endothelial disorder: endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series)

Francesca Polverino  1   2 , Bartolome R Celli  1   2 , Caroline A Owen  1   2
Affiliations

"V体育官网" COPD as an endothelial disorder: endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series)

Francesca Polverino et al. Pulm Circ. 2018 Jan-Mar.

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by chronic expiratory airflow obstruction that is not fully reversible. COPD patients develop varying degrees of emphysema, small and large airway disease, and various co-morbidities VSports手机版. It has not been clear whether these co-morbidities share common underlying pathogenic processes with the pulmonary lesions. Early research into the pathogenesis of COPD focused on the contributions of injury to the extracellular matrix and pulmonary epithelial cells. More recently, cigarette smoke-induced endothelial dysfunction/injury have been linked to the pulmonary lesions in COPD (especially emphysema) and systemic co-morbidities including atherosclerosis, pulmonary hypertension, and chronic renal injury. Herein, we review the evidence linking endothelial injury to COPD, and the pathways underlying endothelial injury and the "vascular COPD phenotype" including: (1) direct toxic effects of cigarette smoke on endothelial cells; (2) generation of auto-antibodies directed against endothelial cells; (3) vascular inflammation; (4) increased oxidative stress levels in vessels inducing increases in lipid peroxidation and increased activation of the receptor for advanced glycation end-products (RAGE); (5) reduced activation of the anti-oxidant pathways in endothelial cells; (6) increased endothelial cell release of mediators with vasoconstrictor, pro-inflammatory, and remodeling activities (endothelin-1) and reduced endothelial cell expression of mediators that promote vasodilation and homeostasis of endothelial cells (nitric oxide synthase and prostacyclin); and (7) increased endoplasmic reticular stress and the unfolded protein response in endothelial cells. We also review the literature on studies of drugs that inhibit RAGE signaling in other diseases (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), or vasodilators developed for idiopathic pulmonary arterial hypertension that have been tested on cell culture systems, animal models of COPD, and/or smokers and COPD patients. .

Keywords: RAGE; apoptosis; oxidative stress; pulmonary endothelium; renal injury. V体育安卓版.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Double contouring of renal capillaries indicative of repetitive endothelial injury in COPD. (a) Severe double contouring in a glomerular capillary in a renal section from a patient with COPD (red arrows). (b) A glomerular capillary in a renal section from a participant without COPD which has no double contouring. (c) A cartoon depicting deposition of additional basement membranes (double contouring) around a glomerular capillary in a patient with COPD (left) versus a normal glomerular capillary in a healthy individual that does not have double contouring (right).
Fig. 2.
Fig. 2.
Mechanisms by which endothelial dysfunction and injury is induced in COPD and leads to end-organ injury affecting the lungs and kidneys in COPD. CS components have direct toxic effects on ECs. CS also leads to increased oxidative stress levels in the lungs and kidneys. Oxidative stress increases the generation of AGEs in these organs, and AGEs bind to and activate RAGE. RAGE signaling in ECs induces endothelial dysfunction and injury (in part, by activating NF-κB), and this process further increases tissue oxidative stress levels and inflammation. RAGE activation also increases RAGE expression which amplifies endothelial injury and end-organ injury. Increased oxidative stress levels in tissues and components of CS (including oxidants and acrolein) also induce endoplasmic reticulum (ER) stress and the unfolded protein response in ECs leading to endothelial dysfunction/injury. CS and oxidative stress both induce senescence of ECs which contributes to endothelial dysfunction. CS changes the pattern of vaso-active mediators produced by ECs. These changes include increased generation of vasoconstrictors (such as endothelin-1) and reduced production of vasodilators such as prostacyclin and NO (due, in part, to reduced expression of prostacyclin synthase and NOS by ECs). Endothelial injury induced by the processes mentioned above leads to the generation of neo-epitopes against which auto-antibodies are generated. The binding of anti-EC antibodies to ECs further increases endothelial injury and amplifies tissue inflammation. The endothelial dysfunction and injury that are induced by all of these pathways lead to apoptosis of ECs. EC apoptosis in the lungs leads to loss of the alveolar walls and emphysema development. EC apoptosis in other organs leads to chronic end-organ injury. CS-induced injury in the kidney (detected as MAB) is characterized by glomerulosclerosis and secondary tubular atrophy and interstitial fibrosis.
Fig. 3.
Fig. 3.
The Renin-Angiotensin-Aldosterone System (RAAS). ACEi and ARBs were originally designed to inhibit the RAAS. Renin is an enzyme that converts angiotensinogen (produced by the liver) to inactive angiotensin I (Ang I). ACE-I is a metalloproteinase which is highly expressed by pulmonary ECs. ACE-I converts inactive Ang I to active angiotensin II (Ang II). Ang II has potent vasoconstrictor activities along with pro-inflammatory and pro-fibrotic activities. ACEi inhibit the enzymatic activity of ACE-I. ARBs compete with Ang II for Ang type I receptors and thereby block Ang II signaling.
Fig. 4.
Fig. 4.
ACEi switch off oxidative stress-AGEs-RAGE signaling in lungs and kidneys to limit end-organ injury in CS-exposed mice. ACEi are known to have anti-oxidant properties. Treating CS-exposed mice with an ACEi reduces oxidative stress levels in the lungs and kidneys, which reduces the AGEs burden in the lungs and kidneys. This in turn, reduces RAGE activation and expression. Reduced RAGE signaling reduces pulmonary and renal endothelial dysfunction and injury, and thereby limits disease progression in the lungs and kidneys of CS-exposed mice.
See this image and copyright information in PMC

References

    1. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary. Am J Respir Crit Care Med 2017; 195: 557–582. - PubMed
    1. Torres-Duque C, Maldonado D, Perez-Padilla R, et al. Biomass fuels and respiratory diseases: a review of the evidence. Proc Am Thorac Soc 2008; 5: 577–590. - PubMed
    1. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007; 370: 765–773. - V体育官网入口 - PubMed
    1. Tuder RM, Petrache I. Pathogenesis of chronic obstructive pulmonary disease. J Clin Invest 2012; 122: 2749–2755. - PMC - PubMed
    1. Miravitlles M, Ribera A. Understanding the impact of symptoms on the burden of COPD. Respir Res 2017; 18: 67. - PMC - PubMed