Abstract
Background Pseudomonas aeruginosa (PA) is one of the most common Gram-negative bacteria causing hospital-acquired pulmonary infection, with high drug resistance and mortality. Therefore, it is urgent to introduce new non-antibiotic treatment strategies. Mesenchymal stem cells (MSCs), as important members of the stem cell family, were demonstrated to alleviate pathological damage in acute lung injury. However, the potential mechanism how MSC alleviate acute lung infection caused by PA remains unclear.ObjectiveThe purpose of this study was to investigate the effects of Adipose-derived mesenchymal stem cells (ASCs) on acute pulmonary infections and the possible mechanisms how ASCs reduce pulmonary inflammation induced by PA.MethodsThe therapeutic and mechanistic effects of ASCs on PA pulmonary infection were evaluated respectively in a murine model as well as in an in vitro model stimulated by PA and co-cultured with ASCs.Results1. ASCs treatment significantly reduced the bacterial load, inflammation of lung tissue and histopathological damage by PA. 2. PA infection mainly activated Nod-like receptor containing a caspase activating and recruitment domain 4 (NLRC4) inflammasome in the lung of mice. ASCs attenuated acute lung infection in mice by inhibiting NLRC4 inflammasome activation. 3. NLRC4−/− mice showed a significant improvement in survival rate and lung bacterial load after PA infection. 4. ASCs mainly increased expression and secretion of STC‐1 in response to PA‐stimulated NLRC4 inflammasome activation.ConclusionsPA infection attenuated macrophage phagocytosis through activation of NLRC4 inflammasome in macrophages, which eventually led to pulmonary inflammatory damage in mouse; ASCs reduced the activation of NLRC4 inflammasome in macrophages induced by PA infection, thereby increasing the phagocytic ability of macrophages, and ultimately improving lung tissue damage in mouse; ASCs may inhibit NLRC4 inflammasome through the secretion of STC-1.
Highlights
Pseudomonas aeruginosa (PA) is one of the Gramnegative bacteria which can cause acute lung infection in immunocompromised humans and can be always isolated from patients suffering from hospital-acquired pneumonia
The main findings of this study can be summarized as follows: 1) PA infection attenuated macrophage phagocytosis through activation of NLRC4 inflammasome in macrophages, which eventually led to pulmonary inflammatory damage in mouse; 2) The beneficial effect of adipose-derived mesenchymal stem cells (ASCs) on PA-induced acute lung infection may result from their ability to suppress NLRC4 inflammasome activation, which resulted in the inhibition of Caspase-1 cleavage and mature IL-1b, IL-18 secretion; 3) The increase of STC-1 production through ASCs could contribute to the inhibitory effect of ASCs on NLRC4 inflammasome activation by PA
We have chosen ASCs and the findings showed that ASCs were effective in reducing broncho-alveolar lavage fluid (BALF) total inflammatory cell count, bacterial loads and inflammatory markers TNF-a and macrophage inflammatory protein (MIP)-2 in both lung and BALF, suggesting that ASCs efficiently reduced pathological damage caused by PA
Summary
Pseudomonas aeruginosa (PA) is one of the Gramnegative bacteria which can cause acute lung infection in immunocompromised humans and can be always isolated from patients suffering from hospital-acquired pneumonia. PA infection is highly prone to drug resistance, and the means of treatment are scarce, the mortality rate is extremely high despite improvements in supportive care and antibiotic use (Neuhauser et al, 2003; Shorr, 2009; Von Baum et al, 2010; Song et al, 2012; Peng et al, 2014; Wang et al, 2014). Previous studies in our group (Mao et al, 2015) have reported that MSC can effectively reduce inflammatory damage and improve the survival rate in lung in a mouse model of pulmonary infection caused by PA. Pseudomonas aeruginosa (PA) is one of the most common Gram-negative bacteria causing hospital-acquired pulmonary infection, with high drug resistance and mortality. The potential mechanism how MSC alleviate acute lung infection caused by PA remains unclear
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