Abstract
RationaleThe effects of mesenchymal stromal cells (MSCs) and MSC‐derived extracellular vesicles (MSC EVs) on multidrug‐resistant pseudomonas aeruginosa (MDR‐PA)‐induced pneumonia remain unclear.Materials and methodsMicroRNA array and RT‐PCR were used to select the major microRNA in MSC EVs. Human peripheral blood monocytes were obtained and isolated from qualified patients. The crosstalk between MSCs/MSC EVs and macrophages in vitro was studied. MDR‐PA pneumonia models were further established in C57BL/6 mice and MSC EVs or miR‐466 overexpressing MSC EVs were intratracheally instilled.ResultsMiR‐466 was highly expressed in MSC EVs. MSCs and miR‐466 promoted macrophage polarization toward Type 2 phenotype through TIRAP‐MyD88‐NFκB axis. Moreover, cocultured macrophages with miR‐466 overexpressing MSCs significantly increased the phagocytosis of macrophages. MSC EVs significantly reduced mortality and decreased influx of BALF neutrophils, proinflammatory factor levels, protein, and bacterial load in murine MDR‐PA pneumonia. Administration of miR‐466 overexpressing MSC EVs further alleviated the inflammatory severity.ConclusionsMSC‐derived EVs containing high levels of miR‐466 may partly participate in host immune responses to MDR‐PA. Both MSCs and MSC EVs have therapeutic effects in treating MDR‐PA‐induced pneumonia.
Highlights
Hospital-acquired pneumonia and ventilator-associated pneumonia generate a significant burden in terms of mortality, morbidity, and hospital costs.[1,2] Notably, multidrugresistant (MDR) bacteria pneumonia can lead to septic shock, acute respiratory distress syndrome, and death.[3]
Ad-mesenchymal stromal cells (MSCs) were pretreated with the neutral sphingomyelinase inhibitor, GW4869 (10 μM) (Sigma-Aldrich),[25] known as the inhibitor of extracellular vesicles (EVs) secretion, for 4 h and adipose-derived MSCs (Ad-MSCs)-derived extracellular vesicles (MSC EVs) were pretreated with anti-CD44 (1 μg/ml) (BD Pharmingen, San Diego, CA), known as inhibitor of EV uptake, for 15 min at 4◦C before coincubating with macrophages
We subsequently determined the expression of the 10 most intensely expressed microRNAs using quantitative real time PCR (Figure 1B) to validate the results from the microRNA array. Both microRNA array and qRT-PCR indicated that miR-466 was highly expressed in Ad-MSC EVs
Summary
Hospital-acquired pneumonia and ventilator-associated pneumonia generate a significant burden in terms of mortality, morbidity, and hospital costs.[1,2] Notably, multidrugresistant (MDR) bacteria pneumonia can lead to septic shock, acute respiratory distress syndrome, and death.[3] Pseudomonas aeruginosa (PA), a Gram-negative rod whose resistance to cephalosporins and carbapenems is a growing pervasive problem, causes hospital-acquired and ventilator-associated pneumonia in 16–20% of critically ill patients.[4] A nationwide study reported that multidrugresistant strains account for 23% of all PA isolates from 2008 to 2010 in China.[5] This antibiotic resistance to PA has resulted in a clinically significant impact on key Intensive Care Unit (ICU) outcomes, including length of hospital stay, cost, and mortality.[3] Development of new antipseudomonal antibiotics is limited and new strategies for treating multidrug-resistant PA (MDR-PA) are needed
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