Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington.
Center for Lung Biology, University of Washington, Seattle, Washington.
Am J Physiol Lung Cell Mol Physiol. 2022 Apr 1;322(4):L607-L616. doi: 10.1152/ajplung.00392.2021. Epub 2022 Feb 23.
We previously showed that pericyte-like cells derived from the FoxD1-lineage contribute to myofibroblasts following bleomycin-induced lung injury. However, their functional significance in lung fibrosis remains unknown. In this study, we used a model of lung pericyte-like cell ablation to test the hypothesis that pericyte-like cell ablation attenuates lung fibrosis in bleomycin-induced lung injury. Lung fibrosis was induced by intratracheal instillation of bleomycin. To ablate pericyte-like cells in the lung, diphtheria toxin (DT) was administered to mice at two different phases of bleomycin-induced lung injury. For early ablation, we coadministered bleomycin with DT and harvested mice at and . To test the effect of ablation after acute injury, we delivered DT 7 days after bleomycin administration. We assessed fibrosis by lung hydroxyproline content and semiquantitative analysis of picrosirius red staining. We performed bronchoalveolar lavage to determine cell count and differential. We also interrogated mRNA expression of fibrosis-related genes in whole lung RNA. Compared with DT-insensitive littermates where pericyte-like cells were not ablated, DT-sensitive animals exhibited no difference in fibrosis at both in the early and late pericyte ablation models. However, early ablation of pericytes reduced acute lung inflammation, as indicated by decreased inflammatory cells. Our data confirm a role for pericytes in regulating pulmonary inflammation in early lung injury.
我们之前的研究表明，FoxD1 谱系来源的周细胞样细胞在博来霉素诱导的肺损伤后有助于肌成纤维细胞的形成。然而，它们在肺纤维化中的功能意义尚不清楚。在这项研究中，我们使用肺周细胞样细胞消融模型来检验以下假设：周细胞样细胞消融可减轻博来霉素诱导的肺损伤中的肺纤维化。通过气管内滴注博来霉素诱导肺纤维化。为了消融肺中的周细胞样细胞，在博来霉素诱导肺损伤的两个不同阶段向 小鼠给予白喉毒素 (DT)。为了进行早期消融，我们将博来霉素与 DT 联合给药，并在 和 时采集小鼠。为了测试急性损伤后的消融效果，我们在博来霉素给药 7 天后给予 DT。我们通过肺羟脯氨酸含量和天狼星红染色的半定量分析来评估纤维化。我们进行支气管肺泡灌洗以确定细胞计数和差异。我们还在全肺 RNA 中检测纤维化相关基因的 mRNA 表达。与未消融周细胞样细胞的 DT 不敏感同窝仔相比，在早期和晚期周细胞消融模型中，DT 敏感动物的纤维化在 时均无差异。然而，周细胞的早期消融减少了急性肺炎症，这表现为炎症细胞减少。我们的数据证实了周细胞在调节早期肺损伤中肺炎症中的作用。
