Li-Fu Li

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory lung disease characterized by persistent airflow limitation and diverse clinical phenotypes. This study investigated circulating inflammatory cytokines and metabolomic profiles in patients with COPD and healthy controls in northeastern Taiwan. Methods: This community-based cross-sectional study included 54 patients with COPD and 41 healthy controls. Circulating cytokines and 189 targeted metabolites were assessed. Benjamini–Hochberg false discovery rate (FDR) correction was applied for multiple testing. Firth penalized logistic regression was used to evaluate cytokine associations with COPD after adjustment for age, sex, smoking status, and body mass index. Results: Patients with COPD were older and more frequently male and ever-smokers than controls. Among quantitatively reliable cytokines, interleukin-17 (IL-17), thymic stromal lymphopoietin, and interferon-γ (IFN-γ) differed significantly between groups after FDR correction. In multivariable Firth analyses, IL-17 (adjusted odds ratio [OR], 1.058; 95% confidence interval [CI], 1.026–1.106) and IFN-γ (adjusted OR, 1.110; 95% CI, 1.047–1.213) remained associated with COPD, with consistent findings in sensitivity analyses. Metabolomic profiling identified alterations in amino acid and phospholipid metabolism, with six of the 11 originally selected metabolites remaining significant after FDR correction. Conclusions: COPD was associated with selective circulating cytokine and metabolic alterations. IL-17 and IFN-γ showed the most consistent associations with COPD after multivariable adjustment and sensitivity analyses. These exploratory findings require validation in larger, better-balanced independent cohorts.

Lipopolysaccharide (LPS) induces pulmonary fibrosis by increasing microvascular permeability and inducing severe inflammation and extracellular matrix accumulation. Mechanical ventilation (MV), although life-sustaining, can increase inflammatory cytokine production, oxidative stress, and alveolar–capillary membrane permeability, leading to ventilator-induced lung injury and pulmonary fibrosis. Lumican is essential for extracellular matrix signaling and wound fibrogenesis in the lungs, cornea, and heart. Lumikine, a peptide corresponding to the 13 C-terminal amino acids of lumican, binds to transforming growth factor-β receptor I/activin receptor-like kinase 5 and promotes wound healing. How the lumican pathway contributes to MV-induced lung inflammation and fibrosis remains unclear. We hypothesized that MV with or without LPS pretreatment would exacerbate lung injury, oxidative stress, and lung fibrosis through the lumican pathway. C57BL/6 mice (wild-type and lumican-deficient) were injected with LPS (intratracheal; 7 days) to induce lung fibrosis and then subjected to MV (10 mL/kg; room air; 8 h). Nonventilated mice served as controls. MV with LPS pretreatment reduced lumican expression and increased microvascular permeability, matrix metalloproteinase-9 level, transforming growth factor-β1 level, α-smooth muscle actin staining intensity, and Masson’s trichrome staining intensity. Lumikine substantially mitigated these fibrotic changes. In conclusion, lumikine attenuates MV-induced exacerbation of pulmonary fibrosis after LPS-induced acute lung injury, partially by modulating the lumican pathway.

Patients with sepsis often receive mechanical ventilation (MV). Continued use of MV may increase overdistention in the lungs, inflammatory mediator production, and inflammatory cell recruitment, eventually causing ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress caused by MV, oxidative stress, and sepsis results in dissociation of GRP78 from transmembrane proteins (PERK, IRE1α, and ATF6) and generates abundant incorrect protein structures. Phosphoinositide 3-kinase-γ (PI3K-γ) has been demonstrated to modulate ER stress associated with sepsis and acute lung injury (ALI). However, the regulatory mechanisms by which ER stress is involved in VILI remain unclear. In this study, MV was hypothesized to augment lung injury and induce ER stress through the PI3K-γ pathway, regardless of endotoxemia. Wild-type or PI3K-γ-deficient C57BL/6 mice were exposed to 30 mL/kg tidal volume of MV with or without endotoxemia for 5 h. The control group comprised nonventilated mice. MV with endotoxemia increased microvascular permeability, lung edema, interleukin-6 and metalloproteinase-9 production, oxidative loads, ER stress biomarkers (GRP78, IRE-1α, PERK), morphological rearrangement, PI3K-γ expression, and bronchial epithelial apoptosis in rodent lungs. The increase in lung injury was substantially reduced in PI3K-γ-deficient mice and in mice administered 4-phenylbutyric acid. In conclusion, MV-augmented ALI after endotoxemia partially depends on the PI3K-γ pathway.

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-β1, oxidative loads, Masson’s trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity (p < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase- (PI3K-) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K- remain unclear. We hypothesized MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K- pathway. Five days after receiving a single bolus of 0.075 units bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-1, oxidative loads, Masson’s trichrome staining, extracellular collagen levels, positive staining of -smooth muscle actin, PI3K- expression, and myonuclear apoptosis (P < 0.05). Decreased diaphragm contractility and peroxisome proliferator activated receptor- coactivator-1 levels were also observed (P < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K- activity (P < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated through PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

Mechanical ventilation (MV) used in patients with acute lung injury (ALI) induces lung inflammation and causes fibroblast proliferation and excessive collagen deposition—a process termed epithelial–mesenchymal transition (EMT). Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating EMT during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, EMT, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase EMT through the PI3K-γ pathway. C57BL/6 mice, either wild-type or PI3K-γ-deficient, were exposed to 6 or 30 mL/kg MV for 5 h after receiving 5 mg/kg AS605240 intraperitoneally 5 days after bleomycin administration. We found that, after bleomycin exposure in wild-type mice, high-tidal-volume MV induced substantial increases in inflammatory cytokine production, oxidative loads, Masson’s trichrome staining level, positive staining of α-smooth muscle actin, PI3K-γ expression, and bronchial epithelial apoptosis (p < 0.05). Decreased respiratory function, antioxidants, and staining of the epithelial marker Zonula occludens-1 were also observed (p < 0.05). MV-augmented bleomycin-induced pulmonary fibrogenesis and epithelial apoptosis were attenuated in PI3K-γ-deficient mice, and we found pharmacological inhibition of PI3K-γ activity through AS605240 (p < 0.05). Our data suggest that MV augmented EMT after bleomycin-induced ALI, partially through the PI3K-γ pathway. Therapy targeting PI3K-γ may ameliorate MV-associated EMT.

ARDS is a potentially lethal syndrome. HLA-DR expression in monocytes reflects their activation and antigen-presenting capacity. However, the correlation between clinical outcomes and HLA-DR expression in alveolar monocytes/macrophages in patients with pneumonia-related ARDS remains unclear. Thus, we determined the trends of HLA-DR and cytokine expressions in alveolar monocytes using repeated measurements to answer this question. Thirty-one pneumonia patients with respiratory failure and ARDS without coronavirus disease 2019 between November 2019 and November 2021 were enrolled in our intensive care unit and three without complete data were excluded. Interleukin (IL)-10, IL-12, and HLA-DR expression in bronchoalveolar lavage (BAL) monocytes were determined on days one and eight. Monocyte HLA-DR expression (mHLA-DR) and CD4 T lymphocytes percentages in BAL cells of survivors increased remarkably after seven days. Monocyte IL-10 expression and monocytes percentages in BAL cells of survivors decreased substantially after seven days. The mHLA-DR was negatively correlated with disease severity scores on day one and eight. In conclusion, serial increases in HLA-DR expression and decreases in IL-10 expression were observed in BAL monocytes of survivors of pneumonia-related ARDS. More studies are needed to confirm this point of view, and then development of a therapeutic agent restoring mHLA-DR and preventing IL-10 production can be considered.

Background and objectives: Acute kidney injury (AKI) is common in critically ill patients, especially those with sepsis. Persistently low human leukocyte antigen (HLA)-DR expression in monocytes reflects the decreased function of antigen-presenting cells, contributing to poor outcomes in sepsis. This study aimed to establish an association between AKI and HLA-DR expression in monocytes of patients with sepsis. Materials and Methods: We detected HLA-DR expression in monocytes and measured plasma levels of S100A12, high-mobility group box 1 (HMGB1), advanced glycation end products (AGE), and soluble receptor for AGE (sRAGE) from septic patients and healthy controls. Results: HLA-DR expression in monocytes was decreased in patients with AKI than in those without AKI (29.8 ± 5.0% vs. 53.1 ± 5.8%, p = 0.005). Compared with AKI patients, the mean monocyte HLA-DR expression in patients with end-stage renal disease was increased without statistical significance. There were no differences in the AGE/sRAGE ratio and plasma levels of S100A12, HMGB1, AGE, and sRAGE between patients with and without AKI. Conclusions: Compared with septic patients without AKI, patients with AKI had significantly lower HLA-DR expression in monocytes. The role of hemodialysis in monocyte HLA-DR expression needs further studies to explore.

The number of patients requiring prolonged mechanical ventilation (PMV) is increasing worldwide, placing a burden on healthcare systems. Therefore, investigating the pathophysiology, risk factors, and treatment for PMV is crucial. Various underlying comorbidities have been associated with PMV. The pathophysiology of PMV includes the presence of an abnormal respiratory drive or ventilator-induced diaphragm dysfunction. Numerous studies have demonstrated that ventilator-induced diaphragm dysfunction is related to increases in in-hospital deaths, nosocomial pneumonia, oxidative stress, lung tissue hypoxia, ventilator dependence, and costs. Thus far, the pathophysiologic evidence for PMV has been derived from clinical human studies and experimental studies in animals. Moreover, recent studies have demonstrated the outcome benefits of pharmacological agents and rehabilitative programs for patients requiring PMV. However, methodological limitations affected these studies. Controlled prospective studies with an adequate number of participants are necessary to provide evidence of the mechanism, prognosis, and treatment of PMV. The great epidemiologic impact of PMV and the potential development of treatment make this a key research field.

Sepsis may induce immunosuppression and result in death. S100A12 can bind to the receptor for advanced glycation end-products (RAGE) and Toll-like receptor (TLR)4 following induction of various inflammatory responses. It is unclear whether S100A12 significantly influences the immune system, which may be associated with sepsis-related mortality. We measured plasma S100A12 levels and cytokine responses (mean ± standard error mean) of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) after S100A12 inhibition in healthy controls and patients with sepsis on days one and seven. Day one plasma soluble RAGE (sRAGE) and S100A12 levels in patients with sepsis were significantly higher than those in controls (2481.3 ± 295.0 vs. 1273.0 ± 108.2 pg/mL, p < 0.001; 530.3 ± 18.2 vs. 310.1 ± 28.1 pg/mL, p < 0.001, respectively). Day seven plasma S100A12 levels in non-survivors were significantly higher than those in survivors (593.1 ± 12.7 vs. 499.3 ± 23.8 pg/mL, p = 0.002, respectively). In survivors, plasma sRAGE levels were significantly decreased after 6 days (2297.3 ± 320.3 vs. 1530.1 ± 219.1 pg/mL, p = 0.009, respectively), but not in non-survivors. Inhibiting S100A12 increased the production of tumor necrosis factor (TNF)-α and interleukin (IL)-10 in stimulated PBMCs for both controls and patients. Therefore, S100A12 plays an important role in sepsis pathogenesis. S100A12 may competitively bind to TLR4 and RAGE, resulting in decreased IL-10 and TNF-α production.