Tumor‐Bearing Status Accelerates Bleomycin‐Induced Pulmonary Inflammation via Endothelial Activation

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Abstract
Background: Drug‐induced lung disease (DILD) is a severe adverse event of cancer treatment. Several clinical reports have demonstrated an association between DILD and tumor progression. However, the underlying mechanism remains unclear. This study aimed to elucidate the role of tumor‐bearing status in the development of DILD. Methods: We prepared a subcutaneous Lewis lung carcinoma (LLC) and KLN205‐bearing model. To trigger DILD, bleomycin (BLM) was administered subcutaneously. mRNA expression associated with endothelial activation (PAI‐1, vWF, and ICAM‐1), inflammatory cell infiltration, and alveolar wall thickness was assessed by using bronchioalveolar lavage fluid (BALF) and lung tissue. Additionally, the role of high‐mobility group box 1 (HMGB1) in tumor‐bearing status was examined. Results: Compared with control mice, LLC‐ and KLN205‐bearing mice showed a tendency toward increased expression of at least one of PAI‐1, vWF, and ICAM‐1 on endothelium, along with inflammatory cell infiltration in the lungs. BLM‐treated mice with LLC showed more inflammatory cell infiltration than BLM‐treated mice, accompanied by a significant increase in PAI‐1, vWF, and ICAM‐1 expression on endothelium. Moreover, BLM‐treated mice with LLC exhibited pronounced alveolar wall thickening. In LLC‐bearing mice, serum HMGB1 levels were significantly higher compared with control mice. Additionally, inflammatory cell infiltration in the lungs tended to be increased by the intraperitoneal injection of HMGB1, which was accompanied by increased expression of vWF and ICAM‐1 on endothelium. Conclusions: This study showed that tumor‐bearing status elicits proinflammatory activation in endothelial cells and inflammatory cell infiltration into the lungs that aggravates DILD caused by BLM.
Funding Information
  • Japan Society for the Promotion of Science (18K15951)
  • Japan Society for the Promotion of Science (22K16194)

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