Disease modeling of pulmonary fibrosis using human pluripotent stem cell-derived alveolar organoids

iPS細胞を用いて作製した肺胞オルガノイドで間質性肺炎の病態再現に成功 --治療満足度の低い間質性肺炎の治療薬開発に向けて前進--. 京都大学プレスリリース. 2021-11-19.Although alveolar epithelial cells play a critical role in the pathogenesis of pulmonary fibrosis, few practical in vitro models exist to study them. Here, we established a novel in vitro pulmonary fibrosis model using alveolar organoids consisting of human pluripotent stem cell-derived alveolar epithelial cells and primary human lung fibroblasts. In this human model, bleomycin treatment induced phenotypes such as epithelial cell-mediated fibroblast activation, cellular senescence, and presence of alveolar epithelial cells in abnormal differentiation states. Chemical screening performed to target these abnormalities showed that inhibition of ALK5 or blocking of integrin αVβ6 ameliorated the fibrogenic changes in the alveolar organoids. Furthermore, organoid contraction and extracellular matrix accumulation in the model recapitulated the pathological changes observed in pulmonary fibrosis. This human model may therefore accelerate the development of highly effective therapeutic agents for otherwise incurable pulmonary fibrosis by targeting alveolar epithelial cells and epithelial-mesenchymal interactions

Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity

体内時計は夜間に自然免疫を発動 --皮膚ケモカインによる自然免疫機構--. 京都大学プレスリリース. 2022-06-16.Biological clocks set for skin immunity. 京都大学プレスリリース. 2022-06-21.The epidermis is the outermost layer of the skin and the body’s primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system

Profile of the ORION (Osaka emergency information Research Intelligent Operation Network system) between 2015 and 2016 in Osaka, Japan: a population-based registry of emergency patients with both ambulance and in-hospital records

Aim: To describe the registry design of the Osaka Emergency Information Research Intelligent Operation Network system (ORION) and its profile of hospital information, patient and emergency medical service characteristics, and in‐hospital outcomes among all patients transported to critical care centers and emergency hospitals in Osaka Prefecture, Japan. Methods: The Osaka Prefecture Government has developed and introduced an information system for emergency patients (the ORION system) that uses a smartphone application (app) for hospital selection by on‐scene emergency medical service personnel and has been accumulating all ambulance records. Since January 2015, medical institutions have obtained information on the diagnosis and outcome of patients transported to medical institutions, and the ORION system merged these data with ambulance records including smartphone app data. Results: From January 2015 to December 2016, 753, 301 eligible patients were registered. The mean age was 58.7 years, and 51.5% of patients were male. After hospital arrival, 39.7% were hospitalized, 58.2% were discharged from hospital, 1.1% changed hospital, and 1.0% died. The most common diagnoses were injury, poisoning, and certain other consequences of external causes. Among the hospitalized patients, 29.2% were continuously hospitalized, 59.0% discharged, 5.2% changed hospital, and 5.8% were dead at 21 days after hospitalization. The most common confirmed diagnosis was diseases of the circulatory system. Conclusion: Using the ORION system developed and operated by Osaka Prefecture since January 2015, we described the epidemiological data of all emergency patients transported to emergency hospitals. Analysis using the ORION database in the future could lead to improvements in the emergency transport system and patient outcomes