The Role of Extracellular Vesicles in Pulmonary Inflammation

PROJECT SUMMARY
Inhalation of airborne particles, especially fine and ultrafine particulate matter (PM) can lead to pulmonary
inflammation, which if not resolved, can cause lung injury and subsequent development of several chronic
diseases. Pulmonary cells release signaling molecules to orchestrate inflammatory responses via cell-cell
communication. One of the essential cell-cell communication mechanisms is via extracellular vesicles (EVs)
and their enclosed cargoes (e.g. microRNAs). Compared to the extracellular signaling molecules, EVs carry
the advantages of protecting the messengers better with their membrane structures and enhancing their effective
concentrations within the vesicular compartment. Thus, identifying the key EV populations responsible for
inflammation regulation and even resolution could greatly help development of therapeutics to alleviate the
damage from the airborne particle-induced inflammation. However, it is difficult to pinpoint the exact types of
EVs and their cargos responsible for inflammation resolution. We hypothesize that by tracing the EVs derived
from pulmonary cells with the special focus on exosomes (Exos) at various time points during inflammation
development, we can identify the specific EV sub-groups responsible for inflammation resolution. Hence, we
proposed to identify Exos and their miRNA cargos in bronchoalveolar lavage (BAL) fluid and lung tissue
in acute and sub-chronic models of pulmonary inflammation (Aim1) and employ NanOstirBar-EnabLed
Single EV Analysis (NOBEL-SEA) to analyze cell specific Exos and enclosed miRNAs (Aim 2). NOBEL-
SEA is a highly innovative advanced analytical technique developed in Dr. Zhong’s group. This technique
enables detection of single EVs and their enclosed miRNA cargos with low sample consumption, high sensitivity
and specificity, and short turn-around time. We will examine the kinetic secretion profiles of Exos in two
inflammation models induced by two nanoparticles that have shown in our previous work to cause either
resolving or persistent inflammation. We will first profile miRNAs from isolated exosomes in BAL fluid and lung
tissue and then apply NOBEL-SEA for analyses of cell-specific Exos and miRNAs. Utilizing two inflammation
models will allow us to study differences in Exos and miRNAs secretion during inflammation initiation and
resolution. Monitoring the dynamic of Exo secretion from different cells and revealing their enclosed miRNAs will
help achieve better understanding on how this EV subtype mediates communication between pulmonary cells
and contributes to the transformation from pro- to anti-inflammatory states. It will pave the way for our long-term
goals in exploring the functions of EVs for alleviation of inflammatory lung diseases induced by exposure to
ultrafine airborne particles.

Grant Number: 5R21ES035983-02
NIH Institute/Center: NIH
Principal Investigator: Andrea Adamcakova-Dodd