Trends in Molecular Medicine
Volume 21, Issue 9, September 2015, Pages 533-542
Journal home page for Trends in Molecular Medicine

Review
Extracellular vesicles in lung microenvironment and pathogenesis

https://doi.org/10.1016/j.molmed.2015.07.004Get rights and content

Highlights

  • Extracellular vesicles (EVs) maintain lung physiological homeostasis.

  • Various triggers can modify EV components and enhance EV secretion in the airway.

  • EVs play important roles in inflammatory airway disease and in lung cancer pathogenesis.

  • Mesenchymal stem cell-derived EVs may have therapeutic potential in lung damage.

Increasing attention is being paid to the role of extracellular vesicles (EVs) in various lung diseases. EVs are released by a variety of cells, including respiratory cells and immune cells, and they encapsulate various molecules, such as proteins and microRNAs, as modulators of intercellular communication. Cancer cell-derived EVs play crucial roles in promoting tumor progression and modifying their microenvironment. By contrast, noncancerous cell-derived EVs demonstrate protective functions against injury, such as tissue recovery and repair, to maintain physiological homeostasis. Airway cells in contact with harmful substances may alter their EV composition and modify the balanced reciprocal interactions with surrounding mesenchymal cells. We summarize the novel findings of EV function in various lung diseases, primarily chronic obstructive pulmonary disease (COPD) and lung cancer.

Section snippets

Secreted vesicles and intercellular communication in the airway microenvironment

Lung diseases are an increasingly important factor in morbidity and mortality rates worldwide. The high incidence of these diseases generally results from inhalation of air pollution, infectious agents, and various toxic antigens with concomitant immune responses. Airway injury from exposure to cigarette smoke and other air pollutants is a major risk factor in the development of various lung diseases, including lung cancer, pulmonary fibrosis, asthma, and COPD. In healthy subjects, bronchial

EV classification and biogenesis

EVs were originally described in 1983 in the laboratory of Rose Johnstone [14]. Currently, a growing body of evidence shows that the production of EVs is a universal feature of cellular biological functions. EVs can be detected in cell culture supernatants and in various biological fluids such as blood, urine, sputum, BAL fluid, synovial fluid, pleural effusions, breast milk, and ascites [15]. The main classes of EVs generally include exosomes, microvesicles (also referred to as ectosomes and

Homeostatic role of EVs in normal airway physiology

Given their isolation from normal extracellular fluids 15, 24, EVs are likely to play important roles in normal lung physiology to maintain homeostasis through intercellular communication in the human airway (Figure 3). In the lungs, a broad range of cell types, including lung epithelial cells, fibroblasts, endothelial cells, tumor cells, stem cells, and various immune cells, can release EVs. In previous reports, EVs derived from lung epithelial cells, endothelial cells, or alveolar macrophages

Emerging functions of EVs in stressed airway physiology

As part of the physiological stress response, exposure to various stimuli can modify EV composition and enhance EV secretion to change the surrounding microenvironment through EV-mediated cell-to-cell communication (Figure 3). EV modification and secretion in stress physiology may be a protective process to eliminate harmful components during adverse conditions such as infection, DNA damage, and smoke exposure 31, 32, 33. For example, Anand et al. investigated the inflammatory functions of

The role of EVs in COPD pathogenesis

Inflammatory airway diseases are airway disorders that are largely related to the presence of persistent inflammation. These related diseases include COPD, pulmonary fibrosis, cystic fibrosis, sarcoidosis, and bronchial asthma, and these diseases are influenced by a combination of environmental, genetic, and epigenetic components [54]. In 2010, Qazi et al. reported that exosomes contribute to the initiation and progression of inflammation in sarcoidosis [55]. To date, some evidence has

The role of EVs in lung cancer pathogenesis

Lung cancer represents an important cause of mortality worldwide. Approximately 85% of all lung cancers are categorized as non-small cell lung cancer (NSCLC). Many therapeutic strategies, including surgery, radiation, chemotherapy, and targeted molecular therapy, are commonly used to treat lung cancer, either alone or in combination. Despite the development of novel molecular therapies [67], the prognosis for lung cancer is still poor, owing primarily to therapeutic resistance and high

Therapeutic roles of mesenchymal stem cell-derived EVs in lung diseases

One major area of interest in EV research is the great potential of various EV functions in therapeutic applications. Currently, stem cell-derived EVs have emerged as a potential solution for tissue repair and wound healing. Some of the most promising stem cell-derived EVs investigated for therapeutic applications in lung tissue regeneration come from mesenchymal stem cells (MSCs).

MSCs can be isolated from adult connective tissues such as bone marrow, umbilical cord, and adipose tissue [92].

Concluding remarks and future perspectives

The involvement of EVs in lung biology has been of great interest over the past few years. In the airway and lung microenvironment, EVs appear to play a key role in intercellular communication under healthy homeostatic regulation conditions as well as in a variety of lung pathologies. EVs derived from a broad range of respiratory cell types micromanage immune responses and disease pathogeneses. Noncancerous cell-derived EVs in the airway demonstrate protective functions against injuries, such

Acknowledgments

This work was supported in part by a Grant-in-Aid for the Third-Term Comprehensive 10 Year Strategy for Cancer Control of Japan, including Awardee of Research Resident Fellowship from the Foundation for Promotion of Cancer Research (Japan); a Grant-in-Aid for scientific research on priority areas in cancer from the Ministry of Education, Culture, Sports, Science and Technology; the Japan Society for the Promotion of Science through the Funding Program for World-Leading Innovative R&D on Science

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