Aspiration of non-infectious gastro-esophageal contents and/or exposure to high concentrations of supplemental oxygen are common events in trauma, anesthetized and/or other critically ill patients. Some of these patients will develop a more serious and protracted pulmonary or systemic inflammatory response leading to acute lung injury (ALI) or worse, acute respiratory distress syndrome (ARDS). Despite recent advances in critical care medicine, overall mortality from ARDS remains unacceptably high, reflecting the lack of specific therapies. Currently, the pathogenesis of this devastating syndrome remains incompletely understood, particularly after the ?non-infectious? or ?sterile? stimuli as mentioned above. The characteristic features of ALI/ARDS include an intense inflammatory response, severe injury to the epithelial / endothelial barrier and alveolar edema. Recent evidence suggests that type I alveolar epithelial (ATI) cell have previously unrecognized functions in innate immunity and are underappreciated players in lung cell- cell cross-talk. Based on our published and preliminary data, we propose that ATI cell-derived microvesicles (ATI-MVs) mediate the intercellular communication between ATI cells and alveolar macrophages (AMs) by the shuttling of selective miRNAs, thus broadcasting distress signals to the recipient cells and initiating the inflammatory cascades. In our previous work, we have reported that epithelial extracellular vesicles (EVs) are inducible and detectable in both mouse broncho-alveolar lavage fluid (BALF). After exposure to aspirated acid or hyperoxia (sterile model of ALI), most of the induced E Vs originate from living ATI epithelial cells and fall into the range of microvesicles (MVs). We further showed that MV-shuttling miRNAs promoted classic macrophage activation and migration in vitro and lung inflammation in vivo. Lipid raft protein caveolin-1 (cav-1) facilitates the selection of miRNA complex in the MVs. Based on our published and the supporting data, we hypothesize that the type I alveolar epithelial MVs mediate non-infectious stimuli-associated inflammation via promoting macrophage activation and recruitment through MV-miRNAs. We also hypothesize that the stimuli-induced cav-1 / hnRNPA2B1 interaction and modification regulate the incorporation of selective miRNAs into MVs. We will test our hypotheses in the following specific aims.
In aim I : we will characterize the secretion of MV-miRNAs and their target cells in the presence of non-infectious stimuli.
In aim II, we will determine the mechanisms of the miRNA selection in MVs.
In aim III, we will determine the functions of MV-miRNAs after non-infectious stimuli.
Severe lung inflammatory responses and respiratory failure often occur in the setting of post-trauma or anesthesia in the patients who aspirate non-infectious gastric contents and/or exposure to high concentrations of oxygen. We hypothesize that the microvesicle-shuttling miRNAs serve as novel targets for the development of diagnostic and therapeutic strategies for severe pulmonary inflammation-associated respiratory failure.
| Lee, Heedoo; Zhang, Duo; Laskin, Debra L et al. (2018) Functional Evidence of Pulmonary Extracellular Vesicles in Infectious and Noninfectious Lung Inflammation. J Immunol 201:1500-1509 |
| Zhang, Duo; Lee, Heedoo; Wang, Xiaoyun et al. (2018) Exosome-Mediated Small RNA Delivery: A Novel Therapeutic Approach for Inflammatory Lung Responses. Mol Ther 26:2119-2130 |
| Lee, Heedoo; Abston, Eric; Zhang, Duo et al. (2018) Extracellular Vesicle: An Emerging Mediator of Intercellular Crosstalk in Lung Inflammation and Injury. Front Immunol 9:924 |
