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Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. However, the role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. Here we report that the absence of the mitochondrial fusion proteins mitofusin1 (MFN1) and mitofusin2 (MFN2) in murine AEC2 cells leads to morbidity and mortality associated with spontaneous lung fibrosis. We uncover a crucial role for MFN1 and MFN2 in the production of surfactant lipids with MFN1 and MFN2 regulating the synthesis of phospholipids and cholesterol in AEC2 cells. Loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase deficiency in AEC2 cells exacerbates bleomycin-induced lung fibrosis. We propose a tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung. Mitochondria of alveolar type 2 epithelial cells (AEC2) in the lung have been suggested to play a role in the development of idiopathic pulmonary fibrosis (IPF). Here the authors show that loss of mitofusin1 and mitofusin2 in murine AEC2 cells leads to the development of lung fibrosis through the regulation of surfactant lipids.

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in type 2 alveolar epithelial (AT2) cells is thought to aggravate alveolar inflammation in acute lung injury. Here, the authors show that the mtLCFAO rate limiting enzyme CPT1a is decreased in AT2 cells in acute respiratory distress syndrome, highlighting the role of mtLCFAO in immunometabolism in this context.

Cell-free DNA (cfDNA) is released from injured cells and aggravates inflammation. Patients with coronavirus disease (COVID-19) often develop pneumonia and respiratory failure, and require oxygen therapy (OT), including mechanical ventilation (MV). It remains unclear whether cfDNA predicts the risk of receiving OT or MV in COVID-19 patients. Therefore, we hypothesized that circulating cfDNA levels could reflect the severity of respiratory failure and determine a therapeutic approach for oxygenation in patients with COVID-19. We analyzed cfDNA levels in serum samples from 95 hospitalized patients with COVID-19 at Showa University Hospital (Tokyo, Japan). cfDNA levels were assessed by measuring the copy numbers of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) using quantitative real-time PCR (qPCR). Both cf-nDNA and cf-mtDNA levels were negatively correlated with adjusted SpO 2 for FiO 2 (SpO 2 /FiO 2 ratio). Elevated cf-nDNA and cf-mtDNA levels were associated with the requirement for OT or MV during patient admission. Multivariate logistic regression analysis revealed that cf-nDNA and cf-mtDNA levels were independent risk factors for OT and MV. These results suggest that both serum cf-nDNA and cf-mtDNA could serve as useful early biomarkers to indicate the necessity of OT or MV in patients with COVID-19.

Heat shock protein (HSP) 40 has emerged as a key factor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin-induced sepsis severity is still unclear. During lipopolysaccharide (LPS)-induced endotoxic shock, HLJ1 knockout mice shows reduced organ injury and IFN-γ (interferon-γ)-dependent mortality. Using single-cell RNA sequencing, we characterize mouse liver nonparenchymal cell populations under LPS stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in distinct immune cell clusters. In CLP models, HLJ1 deletion reduces IFN-γ expression and sepsis mortality rate when mice are treated with antibiotics. HLJ1 deficiency also leads to reduced serum levels of IL-12 in LPS-treated mice, contributing to dampened production of IFN-γ in natural killer cells but not CD4 + or CD8 + T cells, and subsequently to improved survival rate. Adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 and IFN-γ levels and protects the mice from IFN-γ-dependent mortality. In the context of molecular mechanisms, HLJ1 is an LPS-inducible protein in macrophages and converts misfolded IL-12p35 homodimers to monomers, which maintains bioactive IL-12p70 heterodimerization and secretion. This study suggests HLJ1 causes IFN-γ-dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activated IL-12/IFN-γ axis.

Acute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it. A secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS. Of the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); p<0.001] and baseline severity of illness was higher in patients with versus without persistent severe ARDS. Mortality at 60 days [95/232 (41%) versus 233/1299 (18%); p<0.001] was higher, and ventilator-free (p<0.001), intensive care unit-free [0 (0-14) versus 19 (7-23); p<0.001] and non-pulmonary organ failure-free [3 (0-21) versus 20 (1-26); p<0.001] days were fewer in patients with versus without persistent severe ARDS. PaO2:FiO2, FiO2, hepatic failure and positive end-expiratory pressure at enrollment were useful predictive variables. Patients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials.

Here, we demonstrated that the multikinase framework including ERK/AKT and CDK2 promotes the proliferation and invasion of lung adenocarcinoma cell lines through activating DRP1. Our results further uncovered the prognostic significance of DRP1 in early‐stage lung adenocarcinoma, showing that the expression and activation of DRP1 are both significantly associated with an increased risk of postoperative recurrence. Recent studies revealed the role of dynamin‐related protein 1 (DRP1), encoded by the DNM1L gene, in regulating the growth of cancer cells of various origins. However, the regulation, function, and clinical significance of DRP1 remain undetermined in lung adenocarcinoma. Our study shows that the expression and activation of DRP1 are significantly correlated with proliferation and disease extent, as well as an increased risk of postoperative recurrence in stage I to stage IIIA lung adenocarcinoma. Loss of DRP1 in lung adenocarcinoma cell lines leads to an altered mitochondrial morphology, fewer copies of mitochondrial DNA, decreased respiratory complexes, and impaired oxidative phosphorylation. Additionally, the proliferation and invasion are both suppressed in DRP1‐depleted lung adenocarcinoma cell lines. Our data further revealed that DRP1 activation through serine 616 phosphorylation is regulated by ERK/AKT and CDK2 in lung adenocarcinoma cell lines. Collectively, we propose the multikinase framework in activating DRP1 in lung adenocarcinoma to promote the malignant properties. Biomarkers related to mitochondrial reprogramming, such as DRP1, can be used to evaluate the risk of postoperative recurrence in early‐stage lung adenocarcinoma.

Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.

Immunosuppression increases the risk of nosocomial infection in patients with chronic critical illness. This exploratory study aimed to determine the immunometabolic signature associated with nosocomial infection during chronic critical illness. We prospectively recruited patients who were admitted to the respiratory care center and who had received mechanical ventilator support for more than 10 days in the intensive care unit. The study subjects were followed for the occurrence of nosocomial infection until 6 weeks after admission, hospital discharge, or death. The cytokine levels in the plasma samples were measured. Single-cell immunometabolic regulome profiling by mass cytometry, which analyzed 16 metabolic regulators in 21 immune subsets, was performed to identify immunometabolic features associated with the risk of nosocomial infection. During the study period, 37 patients were enrolled, and 16 patients (43.2%) developed nosocomial infection. Unsupervised immunologic clustering using multidimensional scaling and logistic regression analyses revealed that expression of nuclear respiratory factor 1 (NRF1) and carnitine palmitoyltransferase 1a (CPT1a), key regulators of mitochondrial biogenesis and fatty acid transport, respectively, in natural killer (NK) cells was significantly associated with nosocomial infection. Downregulated NRF1 and upregulated CPT1a were found in all subsets of NK cells from patients who developed a nosocomial infection. The risk of nosocomial infection is significantly correlated with the predictive score developed by selecting NK cell-specific features using an elastic net algorithm. Findings were further examined in an independent cohort of COVID-19-infected patients, and the results confirm that COVID-19-related mortality is significantly associated with mitochondria biogenesis and fatty acid oxidation pathways in NK cells. In conclusion, this study uncovers that NK cell-specific immunometabolic features are significantly associated with the occurrence and fatal outcomes of infection in critically ill population, and provides mechanistic insights into NK cell-specific immunity against microbial invasion in critical illness.

Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1β and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation.

Liver kinase B1 (LKB1) is a tumor suppressor, and its loss might lead to activation of the mammalian target of rapamycin (mTOR) and tumorigenesis. This study aimed to determine the clinical relevance of LKB1 gene and protein expression in breast cancer patients. LKB1 protein expression was evaluated using immunohistochemistry in tumors from early breast cancer patients in two Taiwanese medical centers. Data on LKB1 gene expression were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set. The correlations between LKB1 expression, clinicopathologic factors, and patient outcome were analyzed. LKB1 expression was significantly associated with estrogen receptor (ER) expression in 2 of the 4 cohorts, but not with other clinicopathologic factors. LKB1 expression was not a predictor for relapse-free survival, overall survival (OS), or breast cancer-specific survival. In a subgroup analysis of the two Taiwanese cohorts, high LKB1 protein expression was predictive of high OS in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients ( P  = 0.013). Our study results indicate that LKB1 expression is not prognostic in the whole population of breast cancer patients, but it is a potential predictor of OS in the subset of HER2-positive patients