Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach
Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-49281-0 |
| _version_ | 1797388385344552960 |
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| author | Satoshi Kozawa Kengo Tejima Shunki Takagi Masataka Kuroda Mari Nogami-Itoh Hideya Kitamura Takashi Niwa Takashi Ogura Yayoi Natsume-Kitatani Thomas N. Sato |
| author_facet | Satoshi Kozawa Kengo Tejima Shunki Takagi Masataka Kuroda Mari Nogami-Itoh Hideya Kitamura Takashi Niwa Takashi Ogura Yayoi Natsume-Kitatani Thomas N. Sato |
| author_sort | Satoshi Kozawa |
| collection | DOAJ |
| description | Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer’s disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand–receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Importantly, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback loop system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences. |
| first_indexed | 2024-03-08T22:40:03Z |
| format | Article |
| id | doaj.art-1030cbd97fb94eb3b9cb7eeb4bde49c2 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-08T22:40:03Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1030cbd97fb94eb3b9cb7eeb4bde49c22023-12-17T12:13:41ZengNature PortfolioScientific Reports2045-23222023-12-0113111610.1038/s41598-023-49281-0Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approachSatoshi Kozawa0Kengo Tejima1Shunki Takagi2Masataka Kuroda3Mari Nogami-Itoh4Hideya Kitamura5Takashi Niwa6Takashi Ogura7Yayoi Natsume-Kitatani8Thomas N. Sato9Karydo TherapeutiX, Inc.Karydo TherapeutiX, Inc.Karydo TherapeutiX, Inc.National Institutes of Biomedical Innovation, Health and NutritionNational Institutes of Biomedical Innovation, Health and NutritionKanagawa Cardiovascular and Respiratory CenterKanagawa Cardiovascular and Respiratory CenterKanagawa Cardiovascular and Respiratory CenterNational Institutes of Biomedical Innovation, Health and NutritionKarydo TherapeutiX, Inc.Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer’s disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand–receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Importantly, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback loop system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences.https://doi.org/10.1038/s41598-023-49281-0 |
| spellingShingle | Satoshi Kozawa Kengo Tejima Shunki Takagi Masataka Kuroda Mari Nogami-Itoh Hideya Kitamura Takashi Niwa Takashi Ogura Yayoi Natsume-Kitatani Thomas N. Sato Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach Scientific Reports |
| title | Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach |
| title_full | Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach |
| title_fullStr | Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach |
| title_full_unstemmed | Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach |
| title_short | Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach |
| title_sort | latent inter organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach |
| url | https://doi.org/10.1038/s41598-023-49281-0 |
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