BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, chronic interstitial lung disease that is unresponsive to current therapy and often leads to death. However, the rate of disease progression differs among patients. We hypothesized that comparing the gene expression profiles between patients with stable disease and those in which the disease progressed rapidly will lead to biomarker discovery and contribute to the understanding of disease pathogenesis.Methodology and Principal FindingsTo begin to address this hypothesis, we applied Serial Analysis of Gene Expression (SAGE) to generate lung expression profiles from diagnostic surgical lung biopsies in 6 individuals with relatively stable (or slowly progressive) IPF and 6 individuals with progressive IPF (based on changes in DLCO and FVC over 12 months). Our results indicate that this comprehensive lung IPF SAGE transcriptome is distinct from normal lung tissue and other chronic lung diseases. To identify candidate markers of disease progression, we compared the IPF SAGE profiles in stable and progressive disease, and identified a set of 102 transcripts that were at least 5-fold up regulated and a set of 89 transcripts that were at least 5-fold down regulated in the progressive group (P-value≤0.05). The over expressed genes included surfactant protein A1, two members of the MAPK-EGR-1-HSP70 pathway that regulate cigarette-smoke induced inflammation, and Plunc (palate, lung and nasal epithelium associated), a gene not previously implicated in IPF. Interestingly, 26 of the up regulated genes are also increased in lung adenocarcinomas and have low or no expression in normal lung tissue. More importantly, we defined a SAGE molecular expression signature of 134 transcripts that sufficiently distinguished relatively stable from progressive IPF.ConclusionsThese findings indicate that molecular signatures from lung parenchyma at the time of diagnosis could prove helpful in predicting the likelihood of disease progression or possibly understanding the biological activity of IPF.
Chronic neuropathic pain is an unfavourable pathological pain characterised by allodynia and hyperalgesia which has brought considerable trouble to people's physical and mental health, but effective therapeutics are still lacking. MicroRNAs (miRNAs) have been widely studied in the development of neuropathic pain and neuronal inflammation. Among various miRNAs, miR-155 has been widely studied. It is intensively involved in regulating inflammation-associated diseases. However, the role of miR-155 in regulating neuropathic pain development is poorly understood. In the present study, we aimed to investigate whether miR-155 is associated with neuropathic pain and delineate the underlying mechanism. Using a neuropathic pain model of chronic constriction injury (CCI), miR-155 expression levels were markedly increased in the spinal cord. Inhibition of miR-155 significantly attenuated mechanical allodynia, thermal hyperalgesia and proinflammatory cytokine expression. We also demonstrated that miR-155 directly bound with the 3'-untranslated region of the suppressor of cytokine signalling 1 (SOCS1). The expression of SOCS1 significantly decreased in the CCI rat model, but this effect could be reversed by miR-155 inhibition. Furthermore, knockdown of SOCS1 abrogated the inhibitory effects of miR-155 inhibition on neuropathic development and neuronal inflammation. Finally, we demonstrated that inhibition of miR-155 resulted in the suppression of nuclear factor-κB and p38 mitogen-activated protein kinase activation by mediating SOCS1. Our data demonstrate the critical role of miR-155 in regulating neuropathic pain through SOCS1, and suggest that miR-155 may be an important and potential target in preventing neuropathic pain development.
Programmed death 1 ligand 1 (PD-L1) is a negative co-stimulatory molecule in immune responses. Previous reports have indicated that inflammatory cytokines can upregulate the expression of PD-L1 in tumor cells, which in turn suppresses host immune responses. Periodontitis is characterized by persistent inflammation of the periodontium, which is initiated by infection with oral bacteria and results in damage to cells and the matrices of the periodontal connective tissues. In the present study, the expression and function of PD-L1 in periodontal tissue destruction were examined. Periodontal ligament cells (PDLCs) were stimulated by inflammatory cytokines and periodontal pathogens. The expression and function of PD-L1 on the surface of PDLCs was investigated using flow cytometry in vitro. Periodontal disease was induced by the injection of Porphyromonas gingivalis in mouse models. The expression levels of PD-L1 in the periodontal tissues of the mice were analyzed using flow cytometry and immunohistochemistry. PD-L1 was inducibly expressed on the PDLCs by the inflammatory cytokines and periodontal pathogens. The inflammation-induced expression of PD-L1 was shown to cause the apoptosis of activated T lymphocytes and improve the survival of PDLCs. Furthermore, in the mouse model of experimental periodontitis, the expression of PD-L1 in severe cases of periodontitis was significantly lower, compared with that in mild cases. By contrast, no significant differences were observed between the healthy control and severe periodontitis groups. The results of the present study showed that the expression of PD-L1 may inhibit the destruction of periodontal tissues, indicating the involvement of a possible protective feedback mechanism against periodontal infection.
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