Protease-armed, Pathogenic Extracellular Vesicles Link Smoking and Chronic Obstructive Pulmonary Disease.

Rationale: Mounting evidence demonstrates a role for extracellular vesicles (EVs) in driving lung disorders, such as chronic obstructive pulmonary disease (COPD). Although cigarette smoke (CS) is the primary risk factor for COPD, a link between CS and the EVs that could lead to COPD is unknown. Objective: To ascertain whether exposure to CS elicits a proteolytic EV signature capable of driving disease pathogenesis. Methods: Protease expression and enzymatic activity were measured in EVs harvested from the BAL fluid of smoke-exposed mice and otherwise healthy human smokers. Pathogenicity of EVs was examined using pathological tissue scoring after EV transfer into naive recipient mice. Measurements and Main Results: The analyses revealed a unique EV profile defined by neutrophil- and macrophage-derived EVs. These EVs are characterized by abundant surface expression of neutrophil elastase (NE) and matrix metalloproteinase 12 (MMP12), respectively. CS-induced mouse or human-derived airway EVs had a robust capacity to elicit rapid lung damage in naive recipient mice, with an additive effect of NE- and MMP12-expressing EVs. Conclusions: These studies demonstrate the capacity of CS to drive the generation of unique EV populations containing NE and MMP12. The coordinated action of these EVs is completely sufficient to drive emphysematous disease, and their presence could operate as a prognostic indicator for COPD development. Furthermore, given the robust capacity of these EVs to elicit emphysema in naive mice, they provide a novel model to facilitate preclinical COPD research. Indeed, the development of this model has led to the discovery of a previously unrecognized CS-induced protective mechanism against EV-mediated damage.

Interferon-dependent signaling is critical for viral clearance in airway neutrophils.

Neutrophilic inflammation characterizes several respiratory viral infections, including COVID-19-related acute respiratory distress syndrome, although its contribution to disease pathogenesis remains poorly understood. Blood and airway immune cells from 52 patients with severe COVID-19 were phenotyped by flow cytometry. Samples and clinical data were collected at 2 separate time points to assess changes during ICU stay. Blockade of type I interferon and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) signaling was performed in vitro to determine their contribution to viral clearance in A2 neutrophils. We identified 2 neutrophil subpopulations (A1 and A2) in the airway compartment, where loss of the A2 subset correlated with increased viral burden and reduced 30-day survival. A2 neutrophils exhibited a discrete antiviral response with an increased interferon signature. Blockade of type I interferon attenuated viral clearance in A2 neutrophils and downregulated IFIT3 and key catabolic genes, demonstrating direct antiviral neutrophil function. Knockdown of IFIT3 in A2 neutrophils led to loss of IRF3 phosphorylation, with consequent reduced viral catabolism, providing the first discrete mechanism to our knowledge of type I interferon signaling in neutrophils. The identification of this neutrophil phenotype and its association with severe COVID-19 outcomes emphasizes its likely importance in other respiratory viral infections and potential for new therapeutic approaches in viral illness.

Impact of extracellular vesicles on the pathogenesis, diagnosis, and potential therapy in cardiopulmonary disease.

Cardiopulmonary diseases span a wide breadth of conditions affecting both heart and lung, the burden of which is globally significant. Chronic pulmonary disease and cardiovascular disease are two of the leading causes of morbidity and mortality worldwide. This makes it critical to understand disease pathogenesis, thereby providing new diagnostic and therapeutic avenues to improve clinical outcomes. Extracellular vesicles provide insight into all three of these features of the disease. Extracellular vesicles are membrane-bound vesicles released by a multitude, if not all, cell types and are involved in multiple physiological and pathological processes that play an important role in intercellular communication. They can be isolated from bodily fluids, such as blood, urine, and saliva, and their contents include a variety of proteins, proteases, and microRNA. These vesicles have shown to act as effective transmitters of biological signals within the heart and lung and have roles in the pathogenesis and diagnosis of multiple cardiopulmonary diseases as well as demonstrate potential as therapeutic agents to treat said conditions. In this review article, we will discuss the role these extracellular vesicles play in the diagnosis, pathogenesis, and therapeutic possibilities of cardiovascular, pulmonary, and infection-related cardiopulmonary diseases.