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In patients with autoimmune pulmonary alveolar proteinosis, the use of inhaled recombinant granulocyte–macrophage colony-stimulating factor resulted in a significantly better alveolar–arterial oxygen gradient at 25 weeks than the use of placebo. The beneficial effect was not observed in smokers.

Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-β1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-β1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum (ER) stress, and TGF-β1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 (UCP2) and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial–mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for IPF.

Different characteristics of patients with chronic obstructive pulmonary disease (COPD) between Western and Japanese populations have been reported. Risk factors for COPD exacerbation have been reported in Western countries but have not been studied in Japan. We retrospectively examined risk factors for COPD exacerbation. A total of 156 Japanese patients were enrolled, and the records of 136 patients were analyzed. In the exacerbation group (n=60), body mass index, forced vital capacity (FVC), forced expiratory volume in one second (FEV ), the FEV /FVC ratio (FEV /FVC), the percent predicted values of FEV (%FEV ), and serum total protein (TP) and albumin concentrations were lower, and age, mortality rate, frequency of common cold and pneumonia, COPD severity rankings, modified Medical Research Council (mMRC) dyspnea score, and proportions of patients with severe emphysema (>50% of low attenuation area) and receiving long-term oxygen therapy were higher than those in the nonexacerbation group (n=76). However, the proportion of patients with a greater number of eosinophils (≥200/μL and/or ≥2%) and the exhaled nitric oxide concentration did not differ between the two groups. In the univariate analysis, the risk factors for exacerbation were age; long-term oxygen therapy; low FVC, FEV , FEV /FVC and %FEV ; high COPD severity ranking and mMRC score; severe emphysema; hypoproteinemia (<6.5 g/dL); hypoalbuminemia (<3.5 g/dL); leukocytosis; lymphocytopenia; and anemia. In the multivariate analysis, the risk factors were hypoalbuminemia, hypoproteinemia and low FEV . Additionally, in patients in the exacerbation-induced mortality subgroup, age, exacerbation frequency, mMRC score and the proportion of patients with lymphocytopenia were higher, and FVC, %FVC, FEV , serum TP concentration and the lymphocyte number were lower than those in the exacerbation survival subgroup. Malnutrition, airflow limitation and severe emphysema were risks for exacerbation and mortality associated with infection in Japanese patients with COPD.

Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never‐smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains unclear. To gain insight into the pathogenic mechanisms, we sequenced the exomes in the peripheral‐blood DNA from six siblings, four affected and two unaffected siblings, of a family with familial EGFR‐mutant lung adenocarcinoma. We identified a heterozygous missense mutation in MET proto‐oncogene, p.Asn375Lys, in all four affected siblings. Combined with somatic loss of heterozygosity for MET, the higher allele frequency in a Japanese sequencing database supports a causative role of the MET mutation in EGFR‐mutant lung cancer. Functional assays showed that the mutation reduces the binding affinity of MET for its ligand, hepatocyte growth factor, and damages the subsequent cellular processes, including proliferation, clonogenicity, motility and tumorigenicity. The MET mutation was further observed to abrogate the ERBB3‐mediated AKT signal transduction, which is shared downstream by EGFR. These findings provide an etiological view that the MET mutation is involved in the pathogenesis of EGFR‐mutant lung cancer because it generates oncogenic stress that induces compensatory EGFR activation. The identification of MET in a family with familial EGFR‐mutant lung cancer is insightful to explore the pathogenic mechanism of not only familial, but also sporadic EGFR‐mutant lung cancer by underscoring MET‐related signaling molecules. We identified a germline mutation in MET by the whole‐exome sequencing analysis of familial EGFR‐mutant lung cancer. The inactivating mutation in MET potentially generates oncogenic stress that induces compensatory EGFR activation for development of EGFR‐mutant lung cancer. The identification of MET as the gene associated with familial EGFR‐mutant lung cancer will provide valuable insights into the pathogenic mechanisms of not only familial, but also sporadic EGFR‐mutant lung cancer by underscoring MET‐related signaling molecules.

Background: A previous clinical trial for autoimmune pulmonary alveolar proteinosis (APAP) demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation reduced the mean density of the lung field on computed tomography (CT) across 18 axial slice planes at a two-dimensional level. In contrast, in this study, we challenged three-dimensional analysis for changes in CT density distribution using the same datasets. Methods: As a sub-study of the trial, CT data of 31 and 27 patients who received GM-CSF and placebo, respectively, were analyzed. To overcome the difference between various shooting conditions, a newly developed automatic lung field segmentation algorithm was applied to CT data to extract the whole lung volume, and the accuracy of the segmentation was evaluated by five pulmonary physicians independently. For normalization, the percent pixel (PP) in a certain density range was calculated as a percentage of the total number of pixels from −1,000 to 0 HU. Results: The automatically segmented images revealed that the lung field was accurately extracted except for 7 patients with minor deletion or addition. Using the change in PP from baseline to week 25 (ΔPP) as the vertical axis, we created a histogram with 143 HU bins set for each patient. The most significant difference in ΔPP between GM-CSF and placebo groups was observed in two ranges: from −1,000 to −857 and −143 to 0 HU. Conclusion: Whole lung extraction followed by density histogram analysis of ΔPP may be an appropriate evaluation method for assessing CT improvement in APAP.

RationalCorticosteroid therapy plays a key role in the treatment of COVID-19 patients with respiratory failure. However, a rebound phenomenon after steroid cessation rarely occurs. Here, we investigated the clinical features of patients with rebound after steroid therapy.MethodsIn total, 84 patients with COVID-19 treated with corticosteroids were enrolled and analysed retrospectively. A rebound was defined as when a patient’s respiratory status deteriorated after the cessation of corticosteroid therapy, without secondary bacterial infection.ResultsSubjects in the rebound group were more likely to having severe respiratory failure than those in the non-rebound group. While the duration of steroid therapy was longer in the rebound group (8 days vs 10 days, p=0.0009), the dosage of steroid and the timing of the start or termination of steroid therapy did not show any differences between the two groups (p=0.17 and 0.68, respectively). The values of soluble interleukin-2 receptor (sIL-2R) at the baseline and the values of C reactive protein (CRP) or lactate dehydrogenase (LDH) at the end of steroid therapy were significantly higher in the rebound group (937 vs 1336 U/mL; p=0.002, 0.63 vs 3.96 mg/dL; p=0.01 and 278 vs 451 IU/mL; p=0.01, respectively). No patient in the rebound group suffered from thromboses, and the causes of death were exacerbation of COVID-19, ventilator-associated pneumonia or sepsis. The prediction model using baseline features for the rebound phenomenon included four variables of age >68 years, required supplemental oxygen >5 L/min, lymphocyte counts <792 /µL and sIL-2R >1146 U/mL. The discrimination ability of this model was 0.906 (0.755–0.968).ConclusionThese findings suggest that severe respiratory failure has a higher risk for the rebound phenomenon after the cessation of corticosteroids, and the values of sIL-2R, LDH and CRP are useful to assess the probability of developing rebound. A multivariate model was developed to predict rebound risk, which showed acceptable discrimination ability.

Marrow stromal cells (MSCs) isolated from mesenchymal tissues can propagate in vitro to some extent and differentiate into various tissue lineages to be used for cell-based therapies. Cellular senescence, which occurs readily in continual MSC culture, leads to loss of these characteristic properties, representing one of the major limitations to achieving the potential of MSCs. In this study, we investigated the effect of lysophosphatidic acid (LPA), a ubiquitous metabolite in membrane phospholipid synthesis, on the senescence program of human MSCs. We show that MSCs preferentially express the LPA receptor subtype 1, and an abrogation of the receptor engagement with the antagonistic compound Ki16425 attenuates senescence induction in continually propagated human MSCs. This anti-aging effect of Ki16425 results in extended rounds of cellular proliferation, increased clonogenic potential, and retained plasticity for osteogenic and adipogenic differentiation. Expressions of p16(Ink4a), Rb, p53, and p21(Cip1), which have been associated with cellular senescence, were all reduced in human MSCs by the pharmacological inhibition of LPA signaling. Disruption of this signaling pathway was accompanied by morphological changes such as cell thinning and elongation as well as actin filament deformation through decreased phosphorylation of focal adhesion kinase. Prevention of LPA receptor engagement also promoted ubiquitination-mediated c-Myc elimination in MSCs, and consequently the entry into a quiescent state, G(0) phase, of the cell cycle. Collectively, these results highlight the potential of pharmacological intervention against LPA signaling for blunting senescence-associated loss of function characteristic of human MSCs.

Background Relapsing polychondritis (RPC) is a rare progressive autoimmune disease characterized by inflammation in the cartilage of multiple organs. Tracheobronchial involvement appears in nearly half of RPC patients during the course of their disease and represents the main cause of death. Localized tracheobronchial RPC is much rarer, and the pathogenesis remains unclear. Matrilin-1 is a non-collagenous cartilage matrix protein and has been suggested to be a potent autoantigen that induces the airway disease of RPC in animal models. However, the expression of matrilin-1 in tracheobronchial tissue in human remains unclear. Therefore, we examined the expression of matrilin-1 in the tracheal and auricular tissues in a localized tracheobronchial RPC patient. Case presentation A 62-year-old man with systemic sclerosis presented with cough and dyspnea on exertion. The lung function test showed an expiratory flow limitation and chest computed tomography showed diffuse thickness from the trachea to the bronchiole. No other tests showed abnormal findings. To evaluate further, bronchoscopy was performed and endobronchial ultrasonography showed thickness in the fourth-marginal echo layer suggesting inflammation of the cartilage. However, the tracheal biopsy showed no specific findings. The subsequent surgical tracheal biopsies showed inflammatory cell infiltration with destruction of the cartilage. Neither auricular nor nasal deformity, except for a tracheobronchial lesion, was detected. Biopsy from the left auricular cartilage also did not show any inflammatory changes. Finally, we diagnosed the patient with localized tracheobronchial RPC. To address the hypothesis that autoimmunity against matrilin-1 is involved in the pathogenesis of localized tracheobronchial RPC, we evaluated the expression level of matrilin-1 in a tracheal and auricular specimen from this patient. Immunohistochemical staining with anti-matrilin-1 antibody showed matrilin-1 in the tracheal but not in the auricular cartilage. Conclusions We first demonstrated the expression of matrilin-1 in tracheal but not in auricular cartilage in a localized tracheobronchial RPC patient. This result supports the possibility that matrilin-1 is involved in the pathogenesis of localized tracheobronchial RPC. However, this is only one case report and further observations will be needed to confirm this result.

Influenza virus epidemics potentially cause pneumonia, which is responsible for much of the mortality due to the excessive immune responses. The role of costimulatory OX40–OX40 ligand (OX40L) interactions has been explored in the non‐infectious pathology of influenza pneumonia. Here, we describe a critical contribution of OX40L to infectious pathology, with OX40L deficiency, but not OX40 deficiency, resulting in decreased susceptibility to influenza viral infection. Upon infection, bronchiolar progenitors increase in number for repairing the influenza‐damaged epithelia. The OX40L expression is induced on the progenitors for the antiviral immunity during the infectious process. However, these defense‐like host responses lead to more extensive infection owing to the induced OX40L with α‐2,6 sialic acid modification, which augments the interaction with the viral hemagglutinin. In fact, the specific antibody against the sialylated site of OX40L exhibited therapeutic potency in mitigating the OX40L‐mediated susceptibility to influenza. Our data illustrate that the influenza‐induced expression of OX40L on bronchiolar progenitors has pathogenic value to develop a novel therapeutic approach against influenza. Synopsis OX40 ligand (OX40L) is a costimulatory molecule known to be expressed preferentially on antigen‐presenting cells for T‐cell priming. Here, an unprecedented mechanism is found by which OX40L exacerbates influenza pneumonia on bronchiolar progenitors by functioning as the virus receptor. In lower respiratory infection with influenza virus, the number of bronchiolar progenitors is increased for repair of damaged epithelial cells. The OX40L expression is enhanced on the influenza‐expanded bronchiolar progenitors to bolster the host immune response. The infection is paradoxically worsen by accelerated viral binding to the bronchiolar progenitors via the α‐2,6 sialic acid of glycosylated OX40L protein. Graphical Abstract OX40 ligand (OX40L) is a costimulatory molecule known to be expressed preferentially on antigen‐presenting cells for T‐cell priming. Here, an unprecedented mechanism is found by which OX40L exacerbates influenza pneumonia on bronchiolar progenitors by functioning as the virus receptor.