Extracellular vesicles: Their emerging roles in the pathogenesis of respiratory diseases

Alveoli are the basic structure of the lungs, consisting of various types of parenchymal and bone marrow-derived cells including alveolar macrophages. These various types of cells have several important functions; thus, communication between these cells plays an important role in homeostasis as well as in the pathophysiology of diseases in the lungs. For a better understanding of the pathophysiology of lung diseases, researchers have isolated each type of lung cell to investigate the changes in their gene expressions, including their humoral factor or adhesion molecules, to reveal the intercellular communication among these cells. In particular, investigations during the past decade have focused on extracellular vesicles, which are lipid bilayer delimited vesicles released from a cell that can move among various cells and transfer substances, including microRNAs, mRNAs and proteins, thus, functioning as intercellular messengers. Extracellular vesicles can be classified into three general groups: apoptotic bodies, exosomes, and microparticles. Extracellular vesicles, especially exosomes and microparticles, are attracting increasing attention from pulmonologists as tools for understanding pathogenesis and disease diagnosis. Here, we review studies, including our own, on exosomes and microparticles and their roles in both lung homeostasis and the pathogenesis of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive lung diseases, and acute respiratory distress syndrome. This review also addresses the roles of extracellular vesicles in COVID-19, the current global public health crisis.     

Cross-species comparison of the metabolism and excretion of selexipag

1. The metabolism of the prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-333679) has been investigated in liver microsomes and hepatocytes of rats, dogs, and monkeys. MRE-269 formation is the main pathway of selexipag metabolism, irrespective of species. Some interspecies differences were evident for both compounds in terms of both metabolic turnover and metabolic profiles. The metabolism of MRE-269 was slower than that of selexipag in all three species.

2. The metabolism of selexipag was also studied in bile-duct-cannulated rats and dogs after a single oral and intravenous dose of [¹⁴C]selexipag. MRE-269 acyl glucuronide was found in both rat and dog bile. Internal acyl migration reactions of MRE-269 glucuronide were identified in an experiment with the synthetic standard MRE-6001.

3. MRE-269 was the major component in the faeces of rats and dogs. In ex vivo study using rat and dog faeces, selexipag hydrolysis to MRE-269 by the intestinal microflora is considered to be a contributory factor in rats and dogs.

4. A taurine conjugate of MRE-269 was identified in rat bile sample. Overall, selexipag was eliminated via multiple routes in animals, including hydrolysis, oxidative metabolism, conjugation, intestinal deconjugation, and gut flora metabolism.     

Clinicopathological analysis of immunohistochemical expression of CD47 and SIRPα in adult T-cell leukemia/lymphoma

The interaction of CD47 and signal-regulatory protein alpha (SIRPα) induces “don't eat me signal”, leading suppression of phagocytosis. This signal can affect the clinical course of malignant disease. Although CD47 and SIRPα expression are associated with clinicopathological features in several neoplasms, the investigation for adult T-cell leukemia/lymphoma (ATLL) has not been well-documented. This study aimed to declare the association between CD47 and SIRPα expression and clinicopathological features in ATLL. We performed immunostaining on 73 biopsy samples and found that CD47 is primarily expressed in tumor cells, while SIRPα is expressed in non-neoplastic stromal cells. CD47 positive cases showed significantly higher FoxP3 (P = .0232) and lower CCR4 (P = .0214). SIRPα positive cases presented significantly better overall survival than SIRPα negative cases (P = .0132). SIRPα positive cases showed significantly HLA class I (P = .0062), HLA class II (P = .0133), microenvironment PD-L1 (miPD-L1) (P = .0032), and FoxP3 (P = .0229) positivity. In univariate analysis, SIRPα expression was significantly related to prognosis (Hazard ratio [HR] 0.470; 95% confidence interval [CI] 0.253-0.870; P = .0167], although multivariate analysis did not show SIPRα as an independent prognostic factor. The expression of SIRPα on stromal cells reflects activated immune surveillance mechanism in tumor microenvironment and induce good prognosis in ATLL. More detailed studies for gene expression or genomic abnormalities will disclose clinical and biological significance of the CD47 and SIRPα in ATLL.