Combination therapy of iPSC‐derived conditioned medium with ceftriaxone alleviates bacteria‐induced lung injury by targeting the NLRP3 inflammasome

• Published in: Journal of cellular physiology 2022-02, Vol.237 (2), p.1299-1314
• Main Authors: Wann, Shue‐Ren, Chi, Pei‐Ling, Huang, Wei‐Chun, Cheng, Chin‐Chang, Chang, Yun‐Te
• Format: Article
• Language: English
• Subjects: acute lung injury; Acute Lung Injury - chemically induced; Animals; Anti-Bacterial Agents - adverse effects; Antibiotics; Antiinfectives and antibacterials; Attenuation; Biopsy; Bronchus; Ceftriaxone; Ceftriaxone - adverse effects; Combination therapy; Combined treatment; Complex formation; Culture Media, Conditioned - pharmacology; Cytokines; E coli; Escherichia coli; Escherichia coli - metabolism; Humans; Induced infiltration; induced pluripotent stem cells; Induced Pluripotent Stem Cells - metabolism; inflammasome; Inflammasomes; Inflammasomes - metabolism; Inflammation; Interferon; Interleukins; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lungs; Macrophages; Matrix Metalloproteinase 9; Metalloproteinase; Mice; Mice, Inbred C57BL; Mortality; mRNA; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; paracrine effects; Paracrine signalling; Pluripotency; Rats; Sepsis; Sepsis - drug therapy; Stem cells; Survival; Therapy
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30596

The lung is the first and most frequent organ to fail among sepsis patients. The mortality rate of sepsis‐related acute lung injury (ALI) is high. Despite appropriate antimicrobial therapy, no treatment strategies are available for sepsis‐induced ALI. Stem cell‐mediated paracrine signaling is a potential treatment method for various diseases. This study aimed to examine the effects of induced pluripotent stem cell‐derived conditioned medium (iPSC‐CM) combined with antibiotics on ALI in a rat model of Escherichia coli‐induced sepsis. Rats were administered either iPSC‐CM or the vehicle (saline) with antibiotics (ceftriaxone). After 72 h, liquid biopsy, bronchoalveolar lavage fluid (BALF), and tissues were harvested for analysis. Survival rates were observed for up to 3 days. Furthermore, we examined the effects of iPSC‐CM on cytokine production, metalloproteinase 9 (MMP‐9) expression, and NLRP3–ASC interaction in RAW264.7 cells stimulated with lipopolysaccharide/interferon‐γ (LPS/IFN‐γ). Combined treatment of iPSC‐CM with antibiotics significantly improved survival in E. coli‐infected rats (p = 0.0006). iPSC‐CM ameliorated E. coli‐induced infiltration of macrophages, reducing the number of cells in BALF, and suppressing interleukin (IL)‐1β, MIP‐2, IL‐6, and MMP‐9 messenger RNA in lung sections. iPSC‐CM treatment attenuated NLRP3 expression and inhibited NLRP3 inflammasome activation by disrupting NLRP3‐mediated ASC complex formation in LPS/IFN‐γ‐primed RAW264.7 cells. This study reveals the mechanisms underlying iPSC‐CM‐conferred anti‐inflammatory activity in ALI through the attenuation of macrophage recruitment to the lung, thus inactivating NLRP3 inflammasomes in macrophages. iPSC‐CM therapy may be a useful adjuvant treatment to reduce sepsis‐related mortality by ameliorating ALI. Induced pluripotent stem cell‐derived conditioned medium (iPSC‐CM) exerts anti‐inflammatory effects in acute lung injury (ALI) through the attenuation of macrophage recruitment to the lung, thus inactivating NLRP3 inflammasomes in macrophages and being a useful adjuvant treatment method to reduce sepsis‐related mortality by improving ALI. This study makes a significant contribution to the literature because it provides novel insights into the mechanisms underlying iPSC‐CM‐conferred anti‐inflammatory activity in ALI and its potential in treating ALI.