Lipopolysaccharide (LPS), the major outer surface membrane component of Gram-negative bacteria, is one of the main etiological factors in the pathogenesis of several lung diseases, such as chronic obstructive pulmonary disease. The respiratory epithelium and the macrophages comprise the dynamic interface between the outside environment and the host response to bacterial infection via cytokine secretion. In the present study, the mechanisms of LPS induced‑inflammatory response in human lung cells and macrophages were investigated. The effects of LPS exposure on cytokine production, inflammation‑related transcription factors and intracellular signaling pathway activation were assessed in human lung mucoepidermoid carcinoma H292 cells and human macrophage THP‑1 cells. The results demonstrated that LPS markedly increased the expression of interleukin (IL)‑6, IL‑8, tumor necrosis factor (TNF)‑α, matrix metallopeptidase (MMP)‑9 and tissue inhibitor of metalloproteinases‑1 in H292 cells, while it increased the production of IL‑6, IL‑8 and TNF‑α in differentiated THP‑1 cells. In addition, LPS exposure activated nuclear factor (NF)‑κB and activator protein (AP)‑1 signaling in H292 cells, while it activated NF‑κB and signal transducer and activator of transcription (STAT) 3 signaling in THP‑1 cells. Furthermore, treatment with NF‑κB, AP‑1 or STAT3 inhibitors significantly decreased the LPS‑mediated expression of IL‑8 and TNF‑α in these cells, suggesting that these pathways might serve crucial roles in LPS‑induced cytokine expression. In conclusion, LPS stimulation of H292 and THP‑1 cells induced cytokine expression and NF‑κB, mitogen‑activated protein kinase and Janus kinase/STAT3 pathway activation with subsequent nuclear translocation of NF‑κB, AP‑1 and STAT3, which demonstrated potential of the use of NF‑κB, AP‑1 and STAT3 in therapies for conditions and diseases associated with chronic inflammation.

SUMMARY N 6 -methyladenosine (m 6 A) RNA modification is a fundamental determinant of mRNA metabolism, but its role in innate immunity-driven non-alcoholic fatty liver disease (NAFLD) and obesity is not known. Here, we show that myeloid lineage-restricted deletion of the m 6 A “writer” protein Methyltransferase Like 3 (METTL3) prevents age-related and diet-induced development of NAFLD and obesity in mice with improved inflammatory and metabolic phenotypes. Mechanistically, loss of METTL3 results in the differential expression of multiple mRNA transcripts marked with m 6 A, with a notable increase of DNA Damage Inducible Transcript 4 (DDIT4) mRNA level. In METTL3-deficient macrophages, there is a significant downregulation of mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4. Taken together, our findings identify the contribution of METTL3-mediated m 6 A modification of Ddit4 mRNA to macrophage metabolic reprogramming in NAFLD and obesity.

This study aimed to explore the protective effects of a Chinese herbal formula, Jinshui Huanxian formula (JHF), on experimental pulmonary fibrosis and its underlying mechanisms. After being treated with single dose of bleomycin (5 mg/kg) intratracheally, rats were orally administered with JHF and pirfenidone from day 1 to 42, then sacrificed at 7, 14, 28, or 42 days post-bleomycin instillation. JHF ameliorated bleomycin-induced pathological changes, collagen deposition in the rat lung and recovered pulmonary function at different days post-bleomycin instillation. In lungs of JHF-treated rats, the levels of total superoxide dismutase, catalase and glutathione were higher, and myeloperoxidase and methane dicarboxylic aldehyde were lower than those in vehicle-treated rats, respectively. Additionally, JHF inhibited the expression of NADPH oxidase 4 (NOX4) and increased the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) in lung tissues. In vitro, JHF and ruscogenin, a compound of Ophiopogonis Radix contained in JHF, significantly inhibited transforming growth factor β1 (TGF-β1)-induced differentiation of fibroblasts. Furthermore, JHF markedly decreased the level of reactive oxygen species in TGF-β1-induced fibroblast. In line with this, upregulation of NAD(P)H: quinone oxidoreductase 1 and heme oxygenase 1, and downregulation of NOX4 were found in JHF-treated fibroblast induced by TGF-β1. While on the other hand, Nrf2 siRNA could suppress the JHF-mediated inhibition effect on alpha-smooth muscle actin (α-SMA), and FN1 expression induced by TGF-β1 in fibroblasts. These results indicated that JHF performed remarkably therapeutic and long-term effects on pulmonary fibrosis in rat and suppressed the differentiation of fibroblast into myofibroblast through reducing the oxidative response by upregulating Nrf2 signaling. It might provide a new potential natural drug for the treatment of pulmonary fibrosis.

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