Extracellular vesicles (EVs) have been implicated in the pathogenesis of a variety of chronic respiratory diseases, including alpha-1 antitrypsin deficiency (AATD) and idiopathic pulmonary fibrosis (IPF). Their role in disease progression makes them an interesting target for diagnostic and therapeutic interventions.
The multiple potential functions of EVs in these diseases are discussed by Purghè et al in a recent review article published in the journal Biomedicine & Pharmacotherapy.
“Circulating exosomes that contain key mediators of the dysregulated inflammatory process at the basis of respiratory disorders may be targeted by interfering with EV uptake or secretion processes,” they explained. But this is only one of several options.
In fact, exosomes could also be used as drug-delivery vehicles. They could target specific cellular sites while avoiding degradation and evading an uncontrolled immune response. Given their promising roles in the clinical management of chronic respiratory diseases, we will discuss recent findings regarding EVs in AATD and IPF here.
A Possible New Target in AATD
Investigations of the role of EVs in AATD are scarce. In a poster that was scheduled to be presented at the American Thoracic Society 2020 International Conference, Khodayari et al showed that EVs produced by airway epithelial cells in response to cigarette smoke potentiated the proinflammatory phenotype of AATD macrophages.
“We exposed primary small airway epithelial cells to cigarette smoke and isolated and characterized the cigarette smoke-induced EVs,” they explained. “Then, we incubated monocyte-derived macrophages from AATD individuals and healthy controls with isolated control and cigarette smoke-induced EVs.”
They examined the production of cytokines and found the activation of the nuclear factor kappa B (NF-κB) signaling in AATD macrophages, which is known to regulate the expression of several proinflammatory genes.
Recently, another study conducted by Khodayari et al showed that AATD patients with the ZZ genotype have circulating EVs with a potential profibrogenic role.
That study team isolated EVs from the plasma of AATD patients with liver disease and healthy controls. They showed that AATD patients’ EVs promoted the activation of human hepatic stellate cells (HSCs) and contributed to liver inflammation.
The analysis of the vesicles derived from AATD patients and healthy controls showed different compositions, with the ones isolated from AATD patients being enriched in profibrotic cytokines. These included interferon gamma (INF-γ), interleukin-1β (IL1-β), and tumor necrosis factor α (TNF-α), whose levels were correlated with fibrosis in the liver of AATD individuals.
“Given the increased stability of molecules carried by enclosed membrane compartments such as EVs, it is plausible that association of cytokines and chemokines with EVs would imply their increased half-life, as well as their wider distribution to specific target cells and organs distal from the producer cells,” Khodayari et al explained.
In addition, they identified differentially expressed microRNAs (miRNAs). For instance, miR-125a, miR-125b1, miR-125b2, miR-128, and miR-130b, which seem to be involved in liver fibrosis, were upregulated in AATD patients’ EVs.
Though further studies are needed to clarify the role of EVs in AATD pathogenesis, the researchers believe these findings uncovered a potential new target for anti-inflammatory therapy in lung disease and liver fibrosis.
A Clearer Role in Other Lung Diseases
More information is available regarding EVs in IPF than in AATD. An increasing number of studies have investigated both the amount and molecular content of EVs derived in IPF patients in comparison to healthy individuals and patients with other lung diseases, such as chronic obstructive pulmonary disease (COPD) and non-IPF interstitial lung disease.
These EVs have been isolated from a variety of biological sources, including bronchoalveolar lavage fluid (BALF), plasma, and sputum. For instance, BALF samples of IPF patients have a higher amount of EVs, mostly exosomes, than samples of patients with non-IPF interstitial lung disease or healthy individuals.
A recent study published in the International Journal of Molecular Sciences found a distinct miRNA signature in BALF- and lung tissue-derived exosomes of IPF patients when compared to those of nonsmoking controls or COPD patients. The differentially expressed panel of miRNAs included miR-375-3p, miR-200a-3p, miR-200b-3p, miR-141-3p, miR-423-5p, miR-22-3p, miR-320a-3p, miR-320b, and miR-24-3p, among others.
A potential marker of lung fibrosis, miR-21-5p, was also found in EVs isolated from IPF patients’ serum. This miRNA was strongly correlated with disease progression and mortality during a 30-month follow-up period.
Moreover, miR-142-3p was found to be upregulated in both plasma and sputum of IPF patients. This miRNA, identified in macrophage-derived exosomes, has an antifibrotic activity, which is explained, at least in part, by the inhibition of the transforming growth factor beta receptor 1 (TGFβ-R1) in alveolar epithelial cells and lung fibroblasts. miR-142-3p was negatively correlated with lung function, which suggests an association with the severity of lung disease.
Besides differences in the internal content, the exosomes isolated from plasma of IPF patients and healthy controls also exhibit important differences in their surface epitopes. For instance, CD19, CD69, CD8, CD86, CD209, CD133/1, melanoma-associated chondroitin sulfate proteoglycan (MCSP), and receptor tyrosine kinase-like orphan receptor 1 (ROR1) are overexpressed in the surface of IPF patients’ exosomes, while CD42a is downregulated.
Purghè B, Manfredi M, Ragnoli B, Baldanzi G, Malerba M. Exosomes in chronic respiratory diseases. Biomed Pharmacother. 2021;144:112270. doi:10.1016/j.biopha.2021.112270
Khodayari N, Oshins R, Holliday LS, et al. Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo. Cell Commun Signal. 2020;18(1):140. doi:10.1186/s12964-020-00648-0
Khodayari N, Oshins R, Mehrad B, et al. The role of extracellular vesicles in the pathogenesis of cigarette induced alpha-1 antitrypsin deficiency mediated lung inflammation. Am J Respir Crit Care Med. 2020;201:A4017. doi10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A4017
Kaur G, Maremanda KP, Campos M, et al. Distinct exosomal miRNA profiles from BALF and lung tissue of COPD and IPF patients. Int J Mol Sci. 2021;22(21). doi:10.3390/ijms222111830