Thorax Online First, published on August 18, 2016 as 10.1136/thoraxjnl-2016-208895 Editorial ’ the MVs were isolated during the course Thorax: first published as 10.1136/thoraxjnl-2016-208895 on 18 August 2016. Downloaded from Macrophage-derived microvesicles of ALI. And lastly, although the protein cargoes of MVs are important, the role of pathogenic role in acute lung injury mRNA and microRNA in the MVs should not be overlooked. Multiple studies have Jae W Lee shown a transfer of the RNA content between MVs and cells with subsequent translation of the mRNA or microRNA Once considered cellular debris or, more mechanisms of MVs, the authors found leading to a functional effect.2310In the recently, as biomarkers of disease progres- that MVs released by primary cultures of current study, the inflammatory response sion, extracellular vesicles (EVs), com- mouse macrophages primed with LPS to following MVs’ administration in vivo or prised of exosomes, microvesicles (MVs) obtain a pro-inflammatory phenotype also in vitro may be artificially diminished due and apoptotic bodies, released by living induced ICAM-1 expression in MLE-12 to the short incubation time (4 hours), and dying eukaryotic cells are now recog- cells, which was dependent on the TNF which may not be enough for the transla- nised as important mediators of cellular cargo of the MVs. When instilled intratra- tion of the RNA cargo. One wonders, if communication and function.1 EVs are a cheally in naive mice, MVs isolated from the incubation time was increased, heterogeneous population of anucleate macrophages primed with LPS induced whether the inflammatory response would vesicles with a diameter of 100–1000 nm ALI with an increase in influx of neutro- be greater. that are released from intracellular com- phils and cytokines/chemokines (eg, KC), As with any manuscript with findings partments as exosomes or by budding off in lung protein permeability and in the with potential translational impact, more the plasma membrane as MVs in response expression of ICAM-1 on alveolar epithe- questions are raised than answered. How to diverse physiological, pathophysio- lial type I and II cells (Figure 8).7 critical are MVs, exosomes and apoptotic logical or external stimulus. Despite its There are several important findings in bodies in the pathophysiology of ALI importance in various organ injuries and the manuscript by Soni et al7 with clinical compared with the released soluble cancer,23the role of EVs in the pathogen- relevance. First, the clear demonstration factors, for example, cytokines and che- esis of acute lung injury (ALI) is still that MVs released into the injured alveo- mokines, especially in terms of the early – largely unexplored.4 6 In the current issue lus early in ALI were biologically active, inflammatory phase? Soni et al7 found of Thorax, Soni et al7 studied the tem- with the capability to induce an inflamma- minimal levels of IL-1β and IL-6, inflam- poral pattern of EV release in early ALI tory response. All experiments had appro- matory cytokines with significant inflam- and found that MVs from alveolar macro- priate controls such as MVs isolated from matory roles in ALI, in the MVs derived phages were the predominant source and the BALF from mice without injury or the predominantly from alveolar macro- played a significant role as potent initia- supernatant from the washing steps phages. However, Eltom et al and others tors of the inflammatory response in part during the isolation of the MVs as well as have shown that increased airway ATP by the transfer of its cargo, the cytokine low and high doses of LPS to ensure the levels, commonly found in patients with tumour necrosis factor (TNF), to target inflammatory response was specific to the respiratory diseases such as asthma and cells. MVs, not contaminants. Second, in early COPD, can stimulate the release of IL-1β/ http://thorax.bmj.com/ By inducing ALI with intratracheal ALI following intratracheal LPS instilla- IL-18 from EVs released during infec- instillation of lipopolysaccharide (LPS) in tion, alveolar macrophages were the initial tion.11 Can MVs, exosomes or apoptotic C57BL6 mice, the authors found that source of the pro-inflammatory MVs, fol- bodies be targeted and neutralised during MVs released into the injured alveolus lowed soon thereafter by MVs released the early inflammatory phase of ALI, pos- were mainly from alveolar macrophages from alveolar epithelial cells and neutro- sibly preventing the progression to acute initially by flow cytometry, peaking at phils, as determined by flow cytometry. respiratory distress syndrome? Will the 1 hour and followed soon thereafter by And finally, the protein cargo, for molecular cargo of the released MVs, exo- MVs released by alveolar epithelial cells example, TNF, was one of the mechan- somes or apoptotic bodies differ based on on October 2, 2021 by guest. Protected copyright. and neutrophils by 4 hours. More import- isms through which MVs induced an the cause of ALI, for example, LPS versus antly, the MVs in the bronchoalveolar inflammatory response. bacterial pneumonia versus sepsis versus fluid (BALF) at 1 hour contained a sub- There are limitations to the manuscript ventilator-induced lung injury? For stantial amount of TNF but low levels of that require further study to more clearly example, are EVs released by endothelial interleukin (IL)-1β and IL-6 and induced define the role of EVs released during cells potentially more critical in indirect a mouse lung epithelial (MLE)-12 cell line ALI. In the context of early ALI, what are ALI such as following abdominal sepsis to express intercellular adhesion molecule the roles of exosomes or apoptotic bodies for the initiation of the inflammatory 1 (ICAM-1) and secrete KC, a murine in the inflammatory response? What response in the lung12? Although the IL-8 homologue, at 4 hours. Surprisingly, about other cellular sources such as plate- focus of the current study was on MVs alveolar LPS-generated MVs were almost lets, which are a major source of EVs and derived from alveolar macrophages, twice more potent than a dose of LPS play a critical role in ALI?8 The pheno- clearly MVs derived from neutrophils (100 mg/mL) used as a positive control type of the cells may determine the func- have significant roles during ALI. Timár group on the expression of ICAM-1 and tional effects of the released MVs. For et al13 recently found that MVs released secretion of KC by MLE-2 cells example, several studies have shown a key from primary cultures of human neutro- (Figure 6). In experiments to study the role of alveolar macrophages with an anti- phils had bacteriostatic properties. And as inflammatory M2 phenotype in the reso- alluded to as a limitation, the number and lution of ALI.9 The functional effect of phenotype of the EVs will markedly Correspondence to Dr Jae-W Lee, Department of Anesthesiology, University of California San Francisco, the released MV from alveolar macro- change prior to, during and in the reso- 505 Parnassus Ave., P. O. Box 0648, San Francisco, phages may be both pro-inflammatory and lution phase of ALI. Using surface mem- CA 94143, USA; [email protected] anti-inflammatory, depending on when brane markers to identify the source of Lee JW. Thorax Month 2016 Vol 0 No 0 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& BTS) under licence. Editorial fl the MVs by ow cytometry may be inad- 8 Yadav H, Kor DJ. Platelets in the pathogenesis of Thorax: first published as 10.1136/thoraxjnl-2016-208895 on 18 August 2016. Downloaded from equate in describing the biological role of acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2015;309:L915–923. these vesicles. Clearly, more studies are 9D’Alessio FR, Craig JM, Singer BD, et al. Enhanced required and new techniques may need to resolution of experimental ARDS through IL-4- be developed. mediated lung macrophage reprogramming. Am ▸ Despite extensive research and numer- http://dx.doi.org/10.1136/thoraxjnl-2015-208032 J Physiol Lung Cell Mol Physiol 2016;310:L733–46. 10 Zhu YG, Feng XM, Abbott J, et al. Human ous preclinical studies identifying various Thorax 2016;0:1–2. fi mesenchymal stem cell microvesicles for treatment of biological mediators, there are no speci c doi:10.1136/thoraxjnl-2016-208895 Escherichia coli endotoxin-induced acute lung injury pharmacological therapies for acute in mice. Stem Cells 2014;32:116–25. respiratory distress syndrome, the clinical REFERENCES 11 Eltom S, Dale N, Raemdonck KRG, et al. Respiratory form of ALI, and treatment is largely 1 Witwer KW, Buzás EI, Bemis LT, et al. infections cause the release of extracellular veiscles: implications in exacerbation of asthma/COPD. PLoS limited to supportive care and lung- Standardization of sample collection, isolation and 14–16 analysis methods in extracellular vesicle research. ONE 2014;9:e101087. protective ventilation. The manu- J Extracell Vesicles 2013;2:20360. 12 Letsiou E, Sammani S, Zhang W, et al. Pathologic script by Soni et al adds to the under- 2 Das S, Halushka MK. 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