IL-27 regulates the differentiation of follicular helper NKT cells via metabolic adaptation of mitochondria.

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor α chain and contribute to bridging innate and acquired immunity with rapid production of large amounts of cytokines after stimulation. Among effecter subsets of iNKT cells, follicular helper NKT (NKTFH) cells are specialized to help B cells. However, the mechanisms of NKTFH cell differentiation remain to be elucidated. In this report, we studied the mechanism of NKTFH cell differentiation induced by pneumococcal surface protein A and α-galactosylceramide (P/A) vaccination. We found that Gr-1+ cells helped iNKT cell proliferation and NKTFH cell differentiation in the spleen by producing interleukin-27 (IL-27) in the early phase after vaccination. The neutralization of IL-27 impaired NKTFH cell differentiation, which resulted in compromised antibody production and diminished protection against Streptococcus pneumoniae infection by the P/A vaccine. Our data indicated that Gr-1+ cell-derived IL-27 stimulated mitochondrial metabolism, meeting the energic demand required for iNKT cells to differentiate into NKTFH cells. Interestingly, Gr-1+ cell-derived IL-27 was induced by iNKT cells via interferon-γ production. Collectively, our findings suggest that optimizing the metabolism of iNKT cells was essential for acquiring specific effector functions, and they provide beneficial knowledge on iNKT cell-mediated vaccination-mediated therapeutic strategies.

Fibroblast-derived Extracellular Vesicles Induce Lung Cancer Progression in the Idiopathic Pulmonary Fibrosis Microenvironment.

Idiopathic pulmonary fibrosis (IPF) is a progressive aging-related lung disease associated with increased lung cancer risk. Although previous studies have shown that IPF worsens the survival of patients with lung cancer, whether IPF independently affects cancer malignancy and prognosis remains inconclusive. Extracellular vesicles (EVs) have recently emerged as active carriers of molecular biomarkers and mediators of intercellular communication in lung homeostasis and pathogenesis. EV cargo-mediated fibroblast-tumor cell communication might participate in the development and progression of lung cancer by modulating various signaling pathways. In this study, we examined the impact of lung fibroblast (LF)-derived EVs on non-small cell lung cancer (NSCLC) malignancy in the IPF microenvironment. Here, we showed that LFs derived from patients with IPF have phenotypes of myofibroblast differentiation and cellular senescence. Furthermore, we found that IPF LF-derived EVs have markedly altered microRNA compositions and exert proproliferative functions on NSCLC cells. Mechanistically, the phenotype was attributed mainly to the enrichment of miR-19a in IPF LF-derived EVs. As a downstream signaling pathway, mir-19a in IPF LF-derived EVs regulates ZMYND11-mediated c-Myc activation in NSCLC, potentially contributing to the poor prognosis of patients with NSCLC with IPF. Our discoveries provide novel mechanistic insights for understanding lung cancer progression in the IPF microenvironment. Accordingly, blocking the secretion of IPF LF-derived EV miR-19a and their signaling pathways is a potential therapeutic strategy for managing IPF and lung cancer progression.

Impaired TRIM16-Mediated Lysophagy in Chronic Obstructive Pulmonary Disease Pathogenesis.

Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Aging-linked and cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif protein (TRIM) 16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome-selective autophagy, to maintain lysosome function. In this study, we sought to examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis by using human bronchial epithelial cells and lung tissues. CS extract (CSE) induced lysosomal damage via LMP, as detected by galectin-3 accumulation. Autophagy was responsible for modulating LMP and lysosome function during CSE exposure. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in lipofuscin, aggresome and galectin-3 puncta, reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. Human bronchial epithelial cells isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.

Clinical and imaging features of interstitial lung disease in cancer patients treated with trastuzumab deruxtecan.

BACKGROUND: Interstitial lung disease/pneumonitis (ILD/pneumonitis) has been identified as a drug-related adverse event of special interest of trastuzumab deruxtecan (T-DXd), but there were a few reports of T-DXd-related ILD/pneumonitis in clinical practice. METHODS: Between May 25, 2020 (the launch of T-DXd in Japan) and February 24, 2022, there were 287 physician-reported potential ILD/pneumonitis cases from the Japanese post-marketing all-case surveillance. By February 27, 2022, an independent adjudication committee assessed 138 cases and adjudicated 130 cases as T-DXd-related ILD/pneumonitis. The clinical features and imaging characteristics of these cases were evaluated. RESULTS: The majority of adjudicated T-DXd-related ILD/pneumonitis cases were grade 1 or 2 (100/130, 76.9%). The most common radiological pattern types observed were organizing pneumonia patterns (63.1%), hypersensitivity pneumonitis patterns (16.9%), and diffuse alveolar damage (DAD) patterns (14.6%). Eleven cases (8.5%) from 130 resulted in death; the majority of these (8/11, 72.7%) had DAD patterns. The overall proportion of recovery (including the outcomes of recovered, recovered with sequelae, and recovering) was 76.9%, and the median time to recovery was 83.5 days (interquartile range: 42.25-143.75 days). Most cases (59/71, 83.1%) that were treated with corticosteroids were considered responsive to treatment. CONCLUSIONS: This is the first report to evaluate T-DXd-related ILD/pneumonitis cases in clinical practice. Our findings are consistent with previous reports and suggest that patients with DAD patterns have poor outcomes. Evaluation of a larger real-world dataset may further identify predictors of clinical outcome.

Can transbronchial lung cryobiopsy benefit adaptive treatment strategies in connective tissue disease-associated interstitial lung disease?

BACKGROUND: Some patients with connective tissue disease (CTD)-associated interstitial lung disease (ILD) progress to pulmonary fibrosis over their disease course despite initial improvement, potentially indicating a poor prognosis. Transbronchial lung cryobiopsy (TBLC) is a new bioptic approach used in diffuse parenchymal lung diseases. This study of CTD-ILD assessed the utility of TBLC in determining therapeutic decision-making strategies. METHODS: We analyzed medical records of 31 consecutive CTD-ILD patients who underwent TBLC focusing on radio-pathological correlation and disease course. A TBLC-based usual interstitial pneumonia (UIP) score was used that assessed three morphologic descriptors: i) patchy fibrosis, ii) fibroblastic foci, and iii) honeycombing. RESULTS: Among the patients with CTD-ILD, 3 had rheumatoid arthritis, 2 systemic sclerosis, 5 polymyositis/dermatomyositis, 8 anti-synthetase syndrome, 6 Sjögren's syndrome, and 5 had microscopic polyangiitis. Pulmonary function test results showed a mean %FVC of 82.4% and %DLCO of 67.7%. Among the 10 CTD patients and TBLC-proven pathological UIP, 3 patients had prominent inflammatory cells in addition to a framework of UIP, and pulmonary function of most patients improved with anti-inflammatory agents. Six (40%) of 15 patients with TBLC-based UIP score ≥ 1 had a progressive disease course during follow-up, of whom 4 patients received anti-fibrotic agents. CONCLUSIONS: TBLC in patients with CTD-ILD can help determine an appropriate medication strategy, particularly when UIP-like lesions are present. TBLC may be useful when judging which agents to prioritize, anti-inflammatory or anti-fibrotic, is difficult. Moreover, additional information from TBLC may be beneficial when considering early intervention with anti-fibrotic agents in clinical practice.

Frailty and muscle weakness in elderly patients with asthma and their association with cumulative lifetime oral corticosteroid exposure.

BACKGROUND: Frailty is a geriatric syndrome of age-related physiological decline, which is associated with higher mortality and decreased healthy life expectancy, and muscle weakness is one of the presentations of frailty. We investigated an association between lifetime oral corticosteroid (OCS) exposure with frailty and muscle weakness among elderly patients with asthma. METHODS: We studied 203 consecutive elderly outpatients with asthma aged ≥60 years old. They were classified into three groups according to their cumulative lifetime OCS dose (lifetime non-users, lower-dose users, and higher-dose users), which was retrospectively estimated from the response to a structured questionnaire. The prevalence of frailty determined by the Kihon Checklist was compared between the three groups. Hand-grip strength, and lean mass index were also measured as markers of muscle strength. RESULTS: Thirty-seven percent of the patients studied were considered frail. Higher cumulative lifetime OCS exposure was associated with a significantly higher prevalence of frailty (33% in lifetime non-users, 59% in lower-dose users, and 68% in higher-dose users; P for trend <0.005). This was also associated with lower hand-grip strength in both sexes (P for trend; 0.012 in men, and 0.020 in women), and lower lean mass index in men (P for trend 0.002). However, current doses of OCS were not significantly associated with these outcomes. CONCLUSIONS: Cumulative lifetime OCS exposure was associated with a higher prevalence of frailty and muscle weakness. These findings emphasize the importance of minimizing lifetime OCS exposure for the prolongation of healthy life expectancy in patients with asthma.

Anomalous Epithelial Variations and Ectopic Inflammatory Response in Chronic Obstructive Pulmonary Disease.

Phenotypic alterations in the lung epithelium have been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but the precise mechanisms orchestrating this persistent inflammatory process remain unknown because of the complexity of lung parenchymal and mesenchymal architecture. To identify cell type-specific mechanisms and cell-cell interactions among the multiple lung resident cell types and inflammatory cells that contribute to COPD progression, we profiled 57,918 cells from lungs of patients with COPD, smokers without COPD, and never-smokers using single-cell RNA sequencing technology. We predicted pseudotime of cell differentiation and cell-to-cell interaction networks in COPD. Although epithelial components in never-smokers were relatively uniform, smoker groups represent extensive heterogeneity in epithelial cells, particularly in alveolar type 2 (AT2) clusters. Among AT2 cells, which are generally regarded as alveolar progenitors, we identified a unique subset that increased in patients with COPD and specifically expressed a series of chemokines including CXCL1 and CXCL8. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred significantly increased intercellular networks of inflammatory AT2 cells. Our results identify previously unidentified cell subsets and provide an insight into the biological and clinical characteristics of COPD pathogenesis.

Chaperone-Mediated Autophagy Suppresses Apoptosis via Regulation of the Unfolded Protein Response during Chronic Obstructive Pulmonary Disease Pathogenesis.

Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells.

Real-life effectiveness of dupilumab in patients with mild to moderate bronchial asthma comorbid with CRSwNP.

BACKGROUND: Dupilumab, an anti-IL-4α receptor antibody, is a new treatment for severe or refractory asthma. However, real-world evidence on the efficacy of dupilumab in patients with mild to moderate bronchial asthma is lacking. METHODS: We retrospectively evaluated the effects of dupilumab in 62 patients who received dupilumab for eosinophilic sinusitis comorbid with asthma at a single centre in Japan. Type 2 inflammatory markers, ACT, respiratory function tests, and forced oscillation technique (FOT) were analysed before, three months after, and one year after dupilumab administration, mainly in patients with mild to moderate asthma. RESULTS: FEV1, %FEV1, %FVC, treatment steps for asthma and ACT improved significantly after three months of dupilumab treatment. FeNO was markedly decreased, whereas IgE and eosinophil counts showed no significant changes. Pre- and post-treatment respiratory resistance (Rrs) and respiratory reactance (Xrs) correlated significantly with FEV1. Improvement in %FEV1 was associated with higher FeNO and higher serum IgE before dupilumab treatment. CONCLUSION: Dupilumab treatment for sinusitis may improve respiratory functions, asthma symptoms, and asthma treatment reduction, even if the associated bronchial asthma is not severe.

Radiographic features and poor prognostic factors of interstitial lung disease with nivolumab for non-small cell lung cancer.

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non-small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground-glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia-like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia-like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia-like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, three had peritumoral-GGO, and five had a change in radiographic pattern from non-DAD at the onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels.

Treatment and relapse of interstitial lung disease in nivolumab-treated patients with non-small cell lung cancer.

Nivolumab, a human monoclonal antibody against programmed death-1, is approved for the treatment of non-small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune-related adverse event. Currently, there are limited data available on the treatment of nivolumab-induced ILD and its outcome. This retrospective cohort study based on a post-marketing study described the treatment of nivolumab-induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an expert central review committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab-induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87.0%) patients. Of those, 172 (83.1%) patients responded well and survived and 35 (16.9%) died (most died during corticosteroid treatment). A total of nine patients experienced a relapse; at the time of relapse, four patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, three of four patients were taking low doses or had nearly completed dose tapering. All patients (except one, whose treatment was unknown) received corticosteroids for the treatment of relapse, but one patient died. Patients with NSCLC who experience nivolumab-induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD.

Pirfenidone plus inhaled N-acetylcysteine for idiopathic pulmonary fibrosis: a randomised trial.

BACKGROUND: A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown. METHODS: This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide (D LCO) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability. RESULTS: 81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in D LCO, 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups. CONCLUSIONS: Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.

Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis.

The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-ß-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-ß-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-ß signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.

Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis.

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)-induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)-treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain-containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1ß-mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

Clinical utility of thoracoscopy in elderly tuberculous pleurisy patients under local anesthesia.

INTRODUCTION: Diagnosing tuberculous pleurisy is important in Japan because it currently has a moderate tuberculosis prevalence. However, physicians often have difficulty making a diagnosis. It was reported that thoracoscopy under local anesthesia is useful for the diagnosis of tuberculous pleurisy, but there are no reports focusing on elderly patients. METHODS: In this study, the usefulness of thoracoscopy under local anesthesia was evaluated in elderly patients. Among 170 patients who underwent thoracoscopy under local anesthesia at our hospital during 11 years from January 2008 to December 2018, those aged 75 years or older (n = 75) were investigated retrospectively. RESULTS: A total of 55 patients underwent thoracoscopy under local anesthesia for detailed examination of pleural effusion of unknown cause. Of these, 18 were diagnosed as tuberculous pleurisy. The median age was 82 years (range: 75-92 years). The diagnosis of tuberculous pleurisy was made in 11 patients in whom Mycobacterium tuberculosis was detected and in four patients whose pathological findings indicated epithelioid granuloma accompanied by caseous necrosis. Clinical diagnosis was made in the remaining three patients based on thoracoscopic findings of the pleural cavity and a high level of adenosine deaminase in pleural fluid. No serious complications attributable to the examination were observed in any patient. CONCLUSIONS: Thoracoscopy under local anesthesia was useful for the diagnosis of tuberculous pleurisy in elderly patients, with useful information being also obtained for the treatment of tuberculosis.

Prognostic value of radiological findings indeterminate for UIP pattern and anterior upper lobe honeycomb-like lesion in chronic fibrosing interstitial lung disease associated with MPO-ANCA.

BACKGROUND: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is often positive in patients with interstitial lung disease (ILD), which is also often present in patients with microscopic polyangiitis (MPA). A possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. The objective of this study was to determine whether high-resolution computed tomography (HRCT) classification based on recent idiopathic pulmonary fibrosis guideline and specific CT findings can obtain new knowledge of prognostic factors in all MPO-ANCA-positive patients with ILD including both idiopathic ILD and MPA-ILD. METHODS: We analyzed 101 consecutive MPO-ANCA-positive patients with respiratory disease. We assessed the diagnostic accuracy of CT findings, HRCT pattern, and specific radiological signs. Prognostic predictors were determined using Cox regression models. RESULTS: Subjects with chronic ILD included 22 patients with MPA-ILD and 39 patients with ILD but without MPA. A quarter of the patients were radiological indeterminate for usual interstitial pneumonia (UIP) pattern, which resulted in a better prognosis than that for UIP pattern. "Increased attenuation around honeycomb and traction bronchiectasis" and "anterior upper lobe honeycomb-like lesion" were found to be highly frequent radiological findings (39% and 30%, respectively). In addition, the latter finding was a significant negative prognostic factor. CONCLUSIONS: Radiological indeterminate for UIP was a useful HRCT classification in MPO-ANCA-positive patients with ILD. In addition, anterior upper lobe honeycomb-like lesion was found to be specific radiological finding that was a significant prognostic factor. The present results might aid in the assessment of appropriate strategies of diagnosis in these patients.

Regulated Necrosis in Pulmonary Disease. A Focus on Necroptosis and Ferroptosis.

To date, increasing evidence suggests the possible involvement of various types of cell death in lung diseases. The recognized regulated cell death includes necrotic cell death that is immunogenic, releasing damage-associated molecular patterns and driving tissue inflammation. Necroptosis is a well-understood form of regulated necrosis that is executed by RIPK3 (receptor-interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase domain-like protein). Ferroptosis is a newly described caspase-independent form of regulated necrosis that is characterized by the increase of detrimental lipid reactive oxygen species produced via iron-dependent lipid peroxidation. The role of these two cell death pathways differs depending on the disease, cell type, and microenvironment. Moreover, some experimental cell death models have demonstrated shared ferroptotic and necroptotic cell death and the synergistic effect of simultaneous inhibition. This review examines the role of regulated necrotic cell death, particularly necroptosis and ferroptosis, in lung disease pathogenesis in the context of recent insights into the roles of the key effector molecules of these two cell death pathways.

Extracellular Vesicles from Fibroblasts Induce Epithelial-Cell Senescence in Pulmonary Fibrosis.

Aberrant epithelial-mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increased mitochondrial reactive oxygen species and associated mitochondrial damage in lung epithelial cells, leading to activation of the DNA damage response and subsequent epithelial-cell senescence. We showed that IPF LF-derived EVs contain elevated levels of microRNA-23b-3p (miR-23b-3p) and miR-494-3p, which suppress SIRT3, resulting in the epithelial EV-induced phenotypic changes. Furthermore, the levels of miR-23b-3p and miR-494-3p found in IPF LF-derived EVs correlated positively with IPF disease severity. These findings reveal that the accelerated epithelial-cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel paracrine effect of IPF fibroblasts via microRNA-containing EVs.

Chaperone-mediated autophagy receptor modulates tumor growth and chemoresistance in non-small cell lung cancer.

Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosome-associated membrane protein type 2a (LAMP2A) is the key receptor protein of CMA; downregulation of LAMP2A leads to CMA blockade. Although CMA activation has been involved in cancer growth, CMA status and functions in non-small cell lung cancer (NSCLC) by focusing on the roles in regulating chemosensitivity remain to be clarified. In this study, we found that LAMP2A expression is elevated in NSCLC cell lines and patient's tumors, conferring poor survival and platinum resistance in NSCLC patients. LAMP2A knockdown in NSCLC cells suppressed cell proliferation and colony formation and increased the sensitivity to chemotherapeutic drugs in vitro. Furthermore, we found that intrinsic apoptosis signaling is the mechanism of cell death involved with CMA blockade. Remarkably, LAMP2A knockdown repressed tumorigenicity and sensitized the tumors to cisplatin treatment in NSCLC-bearing mice. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes and represents a promising new target against chemoresistant NSCLC.

Successful treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis with triple combination therapy: a case report.

Immune checkpoint inhibitor (ICI)-related pneumonitis is a relatively rare but clinically serious and potentially life-threatening adverse event. The majority of cases can be managed by drug discontinuation, with the administration of corticosteroids added in severe cases. However, worsening of pneumonitis can develop in a subset of patients despite treatment with high doses of corticosteroids. We herein report a case of steroid-refractory ICI-related pneumonitis in a recurrent non-small cell lung cancer (NSCLC) patient treated with pembrolizumab that was successfully improved by triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide). After 3 weeks of initial pembrolizumab administration, the patient was diagnosed with ICI-related pneumonitis. Chest computed tomography (CT) showed patchy distributed bilateral consolidation and ground-glass opacities (GGOs) with traction bronchiectasis and bronchiolectasis resembling the diffuse alveolar damage (DAD) radiographic pattern. Although methylprednisolone pulse therapy was initiated, worsening of respiratory failure resulted in the patient being transferred to the intensive care unit. Because of an insufficient therapeutic response to high-dose corticosteroids, tacrolimus and cyclophosphamide pulse therapy were additively performed as triple combination therapy according to the treatment strategy for pulmonary complications of clinically amyopathic dermatomyositis (CADM). In response to this triple combination therapy, the patient's respiratory condition gradually improved, and chest CT showed the marked amelioration of pulmonary opacities. This is the first report suggesting the efficacy of triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide) for steroid-refractory ICI-related pneumonitis complicated with respiratory failure.