Transforming growth factor-ß1 attenuates inflammation and lung injury with regulating immune function in ventilator-induced lung injury mice.

Ventilator-induced lung injury (VILI) is a lung injury induced or aggravated by mechanical ventilation. Transforming growth factor (TGF)-ß1 is a cytokine that mediates immune function, enabling inflammatory attenuation and tissue repair. Here, we hypothesized that it plays an important role in the attenuation of VILI and inflammation. Ventilation with high tidal volume was performed on C57BL/6 mice to establish a VILI model. After 4 h of ventilation, mice were sacrificed (end of ventilation [EOV]) or extubated for resuscitation at 4 h (post-ventilation 4 h [PV4h]), 8 h (PV8h) and 24 h post-ventilation (PV1d). Recombinant mouse TGF-ß1 (rTGF-ß1) and the neutralization antibody of TGF-ß1 (nTAb) were used in vivo to examine the effect of TGF-ß1 on immune function and inflammatory attenuation in VILI mice. Lung injury was exacerbated at the same trend as the interleukin (IL)-1ß level, peaking at PV1d, whereas IL-6 and tumor necrosis factor (TNF)-α levels gradually reduced. Most active phagosomes, swollen round mitochondria, and cavitating lamellar bodies were observed at PV4h. The CD4+ T cells were significantly increased from PV4h to PV1d, and the CD8a + T cells were higher in the PV4h and PV1d groups; furthermore, the mice in the PV8h group showed highest proportion of CD4+CD8a+ T cells and CD4+/CD8a+ ratio. CD19 + and CD5 + CD19 + B cells in VILI mice began to increase at PV1d. The pulmonary expression of latent and monomer TGF-ß1 increased at PV4h and PV8h. Treatment of rTGF-ß1 only induced high expression of latent and monomer TGF-ß1 at EOV to decrease pulmonary levels of IL-1ß, IL-6, and TNF-α; however, lung injury attenuated from EOV to PV1d. TGF-ß1 induced the delayed elevation of CD4+/CD8a+ T cells ratio and activation of pulmonary CD4+CD8a+ double-positive T cells under certain conditions. Elastic fibers and celluloses, although relatively less proteoglycan, were observed with the overexpression of TGF-ß1 at PV4h and PV8h. In conclusion, TGF-ß1 attenuates the inflammatory response and lung injury of VILI via immune function regulation.

Proteomics of restenosis model in LDLR-deficient hamsters coupled with the proliferative rat vascular smooth muscle cells reveals a new mechanism of vascular remodeling diseases.

A major pathological mechanism involved in vascular remodeling diseases is the proliferation and migration of vascular smooth muscle cells. The lipid distribution of golden hamsters is similar to that of humans, which makes them an excellent study model for studying the pathogenesis and molecular characteristics of vascular remodeling diseases. We performed proteomic analysis on Sprague Dawley rat VSMCs (rVSMCs) and restenosis hamsters with low-density lipoprotein receptor (LDLR) deficiency as part of this study. We have also performed the enrichment analysis of differentially modified proteins in regards to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein domain. 1070 differentially abundant proteins were assessed in rVSMCs before and after platelet-derived growth factor-BB (PDGF-BB) stimulation. Specifically, 1246 proteins displayed significant differences in the restenosis model in LDLR-deficient hamsters. An analysis of crosstalk between LDLR+/- hamsters artery restenosis and proliferating rVSMCs revealed 130 differentially expressed proteins, including 67 up-regulated proteins and 63 downregulated proteins. Enrichment analysis with KEGG showed differential proteins to be mainly concentrated in metabolic pathways. There are numerous differentially abundant proteins but particularly two proteins (phosphofructokinase 1 of liver type and lactate dehydrogenase A) were found to be up-regulated by PDGF-BB stimulation of rVSMCs and in a restenosis model of hamsters with LDLR+/- expression. SIGNIFICANCE: Based on bioinformatics, we have found glycolysis pathway plays an important role in both the LDLR+/- hamsters restenosis model and the proliferation of rVSMCs. Some key glycolysis enzymes may likely be developed either as new biomarkers or drug targets for vascular remodeling diseases.

Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway.

BACKGROUND: In animal models of ventilation-induced lung injury, mitophagy triggers mitochondria damage and the release of mitochondrial (mt) DNA, which activates inflammation. However, the mechanism of this process is unclear. METHODS: A model of cyclic stretching (CS)-induced lung epithelial cell injury was established. The genetic intervention of phosphatase and tensin homolog-induced kinase 1 (PINK1) expression via lentivirus transfection was used to identify the relationship between PINK1-mediated mitophagy and mtDNA release in stretching-induced inflammatory response and injury. Pharmacological inhabitation of Toll-like receptor 9 (TLR9) and myeloid differentiation factor 88 (MyD88) expression was performed via their related inhibitors, while pre-treatment of exogenous mtDNA was used to verify the role of mtDNA in stretching-induced inflammatory response and injury. RESULTS: Using a cell culture model of CS, we found that knocking down PINK1 in lung epithelial cells reduced mitophagy activation and mtDNA release, leading to milder inflammatory response and injury; conversely, up-regulating PINK1 exacerbated stretching-induced inflammation and injury, and similar effects were observed by upregulating TLR9 to induce expression of MyD88 and nuclear factor-κB (NF-κB)/p65. Down-regulating MyD88 protected lung epithelial cells from stretching injury and decreased NF-κB/p65 expression. CONCLUSION: These findings suggest that PINK1-dependent mitophagy and associated TLR9 activation is indeed a major factor in stretch-induced cell injury via a mechanism in which released mtDNA activates TLR9 and thereby the MyD88/NF-κB pathway. Inhibiting this process may be a therapeutic approach to prevent inflammation and cell injury in patients on mechanical ventilation.

Clinical impact of type 2 diabetes mellitus on outcomes after one-lung ventilation during thoracic surgery: a retrospective cohort study.

BACKGROUND: The preoperative presence of diabetes mellitus (DM) has been recently demonstrated to be a risk factor for adverse events after thoracic surgery. However, the specific effects of presence of DM preoperatively on thoracic surgery is not known. This study aimed to investigate the association between preoperative DM and clinical outcomes and the short-term survival rates after thoracic surgery. METHODS: In this retrospective, observational, and matched-pair analysis study, patients receiving thoracic surgery from a tertiary university hospital in 2 consecutive years were grouped as either type 2 DM (T2DM) or controlled within the first 24 hours after surgery. Multivariate Cox regression was conducted to investigate the impact of T2DM within the first 24 hours of admission on in-intensive care unit (ICU) and hospital survival. RESULTS: Among the included thoracic patients, 41 (8.4%) had T2DM and 450 (91.6%) did not have T2DM. In the single-factor analyses, T2DM patients were shown to have a higher preoperative white blood cells (WBCs) count, increased release of immunoglobulin A, complement C3 and C4, impaired kidney function with high level of urea, and low expression of alanine aminotransferase (ALT) and monoamine oxidase (MAO). In multivariate analyses, the preoperative urea level was associated with a low-grade risk of dying for the ICU survival time. In contrast, preoperative complement C3 level favored a positive contribution in-ICU survival. Besides the complement C3 level, immunoglobulin A level remained a positive contribution in regression models of hospital survival. CONCLUSIONS: Pre-admission T2DM was not associated with an increased in-ICU and hospital mortality among patients with thoracic surgery. Furthermore, they were accompanied by impaired kidney function, activated inflammation and liver function.

Non-intubated anesthesia in patients undergoing video-assisted thoracoscopic surgery: A systematic review and meta-analysis.

INTRODUCTION: Non-intubated anesthesia (NIA) has been proposed for video-assisted thoracoscopic surgery (VATS), although how the benefit-to-risk of NIA compares to that of intubated general anesthesia (IGA) for certain types of patients remains unclear. Therefore, the aim of the present meta-analysis was to understand whether NIA or IGA may be more beneficial for patients undergoing VATS. METHODS: A systematic search of Cochrane Library, Pubmed and Embase databases from 1968 to April 2019 was performed using predefined criteria. Studies comparing the effects of NIA or IGA for adult VATS patients were considered. The primary outcome measure was hospital stay. Pooled data were meta-analyzed using a random-effects model to determine the standard mean difference (SMD) with 95% confidence intervals (CI). RESULTS AND DISCUSSION: Twenty-eight studies with 2929 patients were included. The median age of participants was 56.8 years (range 21.9-76.4) and 1802 (61.5%) were male. Compared to IGA, NIA was associated with shorter hospital stay (SMD -0.57 days, 95%CI -0.78 to -0.36), lower estimated cost for hospitalization (SMD -2.83 US, 95% CI -4.33 to -1.34), shorter chest tube duration (SMD -0.32 days, 95% CI -0.47 to -0.17), and shorter postoperative fasting time (SMD, -2.76 days; 95% CI -2.98 to -2.54). NIA patients showed higher levels of total lymphocytes and natural killer cells and higher T helper/T suppressor cell ratio, but lower levels of interleukin (IL)-6, IL-8 and C-reactive protein (CRP). Moreover, NIA patients showed lower levels of fibrinogen, cortisol, procalcitonin and epinephrine. CONCLUSIONS: NIA enhances the recovery from VATS through attenuation of stress and inflammatory responses and stimulation of cellular immune function.