Functional Evidence of Pulmonary Extracellular Vesicles in Infectious and Noninfectious Lung Inflammation

Abstract

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a highly complex process that can be triggered by both noninfectious (sterile) and infectious stimuli. Inflammatory lung responses are one of the key features in the pathogenesis of this devastating syndrome. How ALI/ARDS-associated inflammation develops remains incompletely understood, particularly after exposure to sterile stimuli. Emerging evidence suggests that extracellular vesicles (EVs) regulate intercellular communication and inflammatory responses in various diseases. In this study, we characterized the generation and function of pulmonary EVs in the setting of ALI/ARDS, induced by sterile stimuli (oxidative stress or acid aspiration) and infection (LPS/Gram-negative bacteria) in mice. EVs detected in bronchoalveolar lavage fluid (BALF) were markedly increased after exposure of animals to both types of stimuli. After sterile stimuli, alveolar type-І epithelial cells were the main source of the BALF EVs. In contrast, infectious stimuli-induced BALF EVs were mainly derived from alveolar macrophages (AMs). Functionally, BALF EVs generated in both the noninfectious and infectious ALI models promoted the recruitment of macrophages in in vivo mouse models. Furthermore, BALF EVs differentially regulated AM production of cytokines and inflammatory mediators, as well as TLR expression in AMs in vivo. Regardless of their origin, BALF EVs contributed significantly to the development of lung inflammation in both the sterile and infectious ALI. Collectively, our results provide novel insights into the mechanisms by which EVs regulate the development of lung inflammation in response to diverse stimuli, potentially providing novel therapeutic and diagnostic targets for ALI/ARDS.

Extracellular vesicles: novel communicators in lung diseases

“…In acid-induced ALI, the elevated levels of miR-17 and 221 in lung epitheliumderived MVs were found to be involved in the activation and recruitment of macrophages [239]. Both sterile stimuli (oxidative stress or acid aspiration) and infection (LPS/ Gram-negative bacteria) lead to increase in BALF EVs, however, the source for these EVs differed [240]. BALF EVs from sterile stimuli was mainly from alveolar type-І epithelial cells, whereas infection-induced BALF EVs were from alveolar macrophages (AMs).…”

Retracted Article: Macrophage-derived exosomes mediate osteosarcoma cell behavior by activating AKT signaling

“…For the nanoparticle tracking analysis (NTA), ow cytometric analysis was performed as described previously. 15 In summary, the puried exosomes that were derived from THP1 cells were inltrated within 10 mL of aldehyde/sulfate latex beads (Thermo Fisher Scientic) for 2 h. Aer blocking, the beadbound exosomes were xed, followed by incubating them with antibodies against CD81 and CD63, as indicated. The images were obtained using a Nanosight NS500, following the manufacturer's instructions.…”

Exosomes in Sepsis

“…In sepsis, circulating inflammatory molecules damage the alveolar-capillary barrier to induce the influx of pulmonary edema fluid and lung injury (62). Exosomes were increased in the bronchoalveolar lavage fluid (BALF) of infectious and non-infectious ALI mice (63). Caspase-1 encapsulated in exosomes released from LPS-challenged macrophages induced lung endothelial cell apoptosis, indicating their contribution to the disruption of the alveolar-capillary barrier (30).…”