CD146 deficiency aggravates chronic obstructive pulmonary disease via the increased production of S100A9 and MMP-9 in macrophages. International immunopharmacology Chronic obstructive pulmonary disease (COPD) is a leading cause of global death. As a molecule beyond adhesion, CD146 is involved in COPD pathogenesis. However, the mechanisms of CD146 in COPD remain largely elusive. We hypothesized that CD146 regulates the production of matrix metalloproteinase-9 (MMP-9) in macrophages and thereby contributes to COPD. Here, we constructed a murine model of COPD using lipopolysaccharide (LPS) and porcine pancreatic elastase (PPE). In COPD-like mice, LPS and PPE decreased the pulmonary expression of CD146. MMP-9 expression and bioactivity were increased in CD146 knockout COPD-like mice. In vitro, LPS decreased CD146 expression in macrophages. With or without LPS challenge, CD146-defective macrophages produced more MMP-9. Transcriptome analysis based on next-generation sequencing (NGS) revealed that S100A9 regulated MMP-9 production in CD146-defective macrophages. Targeting S100A9 with paquinimod decreased lung inflammation and alleviated alveolar destruction in COPD-like mice. Collectively, our study suggests that CD146 negatively regulates MMP-9 production in macrophages via the S100A9 pathway in COPD. 10.1016/j.intimp.2023.111410

Comprehensive Targeted Metabolomic Study in the Lung, Plasma, and Urine of PPE/LPS-Induced COPD Mice Model. International journal of molecular sciences (1) Background: Progression of chronic obstructive pulmonary disease (COPD) leads to irreversible lung damage and inflammatory responses; however, biomarker discovery for monitoring of COPD progression remains challenging. (2) Methods: This study evaluated the metabolic mechanisms and potential biomarkers of COPD through the integrated analysis and receiver operating characteristic (ROC) analysis of metabolic changes in lung, plasma, and urine, and changes in morphological characteristics and pulmonary function in a model of PPE/LPS-induced COPD exacerbation. (3) Results: Metabolic changes in the lungs were evaluated as metabolic reprogramming to counteract the changes caused by the onset of COPD. In plasma, several combinations of phenylalanine, 3-methylhistidine, and polyunsaturated fatty acids have been proposed as potential biomarkers; the α-aminobutyric acid/histidine ratio has also been reported, which is a novel candidate biomarker for COPD. In urine, a combination of succinic acid, isocitric acid, and pyruvic acid has been proposed as a potential biomarker. (4) Conclusions: This study proposed potential biomarkers in plasma and urine that reflect altered lung metabolism in COPD, concurrently with the evaluation of the COPD exacerbation model induced by PPE plus LPS administration. Therefore, understanding these integrative mechanisms provides new insights into the diagnosis, treatment, and severity assessment of COPD. 10.3390/ijms23052748

Experimental animal models for COPD: a methodological review. Tobacco induced diseases INTRODUCTION:Chronic obstructive pulmonary disease (COPD) is a progressive disorder that makes the breathing difficult and is characterized by pathological conditions ranging from chronic inflammation to tissue proteolysis. With regard to ethical issues related to the studies on patients with COPD, the use of animal models of COPD is inevitable. Animal models improve our knowledge about the basic mechanisms underlying COPD physiology, pathophysiology and treatment. Although these models are only able to mimic some of the features of the disease, they are valuable for further investigation of mechanisms involved in human COPD. METHODS:We searched the literature available in Google Scholar, PubMed and ScienceDirect databases for English articles published until November 2015. For this purpose, we used 5 keywords for COPD, 3 for animal models, 4 for exposure methods, 3 for pathophysiological changes and 3 for biomarkers. One hundred and fifty-one studies were considered eligible for inclusion in this review. RESULTS:According to the reviewed articles, animal models of COPD are mainly induced in mice, guinea pigs and rats. In most of the studies, this model was induced by exposure to cigarette smoke (CS), intra-tracheal lipopolysaccharide (LPS) and intranasal elastase. There were variations in time course and dose of inducers used in different studies. The main measured parameters were lung pathological data and lung inflammation (both inflammatory cells and inflammatory mediators) in most of the studies and tracheal responsiveness (TR) in only few studies. CONCLUSION:The present review provides various methods used for induction of animal models of COPD, different animals used (mainly mice, guinea pigs and rats) and measured parameters. The information provided in this review is valuable for choosing appropriate animal, method of induction and selecting parameters to be measured in studies concerning COPD. 10.1186/s12971-017-0130-2

Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. The Lancet. Respiratory medicine BACKGROUND:Chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity, disability, and mortality worldwide. We aimed to estimate global, regional, and national COPD prevalence and risk factors to guide policy and population interventions. METHODS:For this systematic review and modelling study, we searched MEDLINE, Embase, Global Health, and CINAHL, for population-based studies on COPD prevalence published between Jan 1, 1990, and Dec 31, 2019. We included data reported using the two main case definitions: the Global Initiative for Chronic Obstructive Lung Disease fixed ratio (GOLD; FEV/FVC<0·7) and the lower limit of normal (LLN; FEV/FVC<LLN). We employed a multilevel multivariable mixed-effects meta-regression approach to generate the age-specific and sex-specific prevalence of COPD in 2019 for high-income countries (HICs) and low-income and middle-income countries (LMICs) according to the World Bank definition. Common risk factors for GOLD-COPD were evaluated using a random-effects meta-analysis. FINDINGS:We identified 162 articles reporting population-based studies conducted across 260 sites in 65 countries. In 2019, the global prevalence of COPD among people aged 30-79 years was 10·3% (95% CI 8·2-12·8) using the GOLD case definition, which translates to 391·9 million people (95% CI 312·6-487·9), and 7·6% (5·8-10·1) using the LLN definition, which translates to 292·0 million people (219·8-385·6). Using the GOLD definition, we estimated that 391·9 million (95% CI 312·6-487·9) people aged 30-79 years had COPD worldwide in 2019, with most (315·5 million [246·7-399·6]; 80·5%) living in LMICs. The overall prevalence of GOLD-COPD among people aged 30-79 years was the highest in the Western Pacific region (11·7% [95% CI 9·3-14·6]) and lowest in the region of the Americas (6·8% [95% CI 5·6-8·2]). Globally, male sex (OR 2·1 [95% CI 1·8-2·3]), smoking (current smoker 3·2 [2·5-4·0]; ever smoker 2·3 [2·0-2·5]), body-mass index of less than 18·5 kg/m (2·2 [1·7-2·7]), biomass exposure (1·4 [1·2-1·7]), and occupational exposure to dust or smoke (1·4 [1·3-1·6]) were all substantial risk factors for COPD. INTERPRETATION:With more than three-quarters of global COPD cases in LMICs, tackling this chronic condition is a major and increasing challenge for health systems in these settings. In the absence of targeted population-wide efforts and health system reforms in these settings, many of which are under-resourced, achieving a substantial reduction in the burden of COPD globally might remain a difficult task. FUNDING:National Institute for Health Research and Health Data Research UK. 10.1016/S2213-2600(21)00511-7