Sharma Guru Prasad, Frei Anne, Fish Brian, Gasperetti Tracy, Veley Dana, Szalewski Nathan, Nissen Austen, Himburg Heather A
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, United States.
Cancer Center, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Physiol. 2023 May 19;14:1191237. doi: 10.3389/fphys.2023.1191237. eCollection 2023.
In experimental animal models, biological sex-differences in the manifestation and severity of normal tissue radiation injury have been well-documented. Previously we demonstrated male and female rats have differential and highly reproducible responses to high-dose partial body irradiation (PBI) with male rats having greater susceptibility to both gastrointestinal acute radiation syndrome (GI-ARS) and radiation pneumonitis than female rats. In the current study, we have investigated whether differential expression of the renin-angiotensin system (RAS) enzymes angiotensin converting enzyme (ACE) and ACE2 contribute to the observed sex-related differences in radiation response. During the period of symptomatic pneumonitis, the relative ratio of ACE to ACE2 (ACE/ACE2) protein in the whole lung was significantly increased by radiation in male rats alone. Systemic treatment with small molecule ACE2 agonist diminazene aceturate (DIZE) increased lung ACE2 activity and reduced morbidity during radiation pneumonitis in both sexes. Notably DIZE treatment also abrogated morbidity in male rats during GI-ARS. We then evaluated the contribution of the irradiated bone marrow (BM) compartment on lung immune cell infiltration and ACE imbalance during pneumonitis. Transplantation of bone marrow from irradiated donors increased both ACE-expressing myeloid cell infiltration and immune ACE activity in the lung during pneumonitis compared to non-irradiated donors. Together, these data demonstrate radiation induces a sex-dependent imbalance in the renin-angiotensin system enzymes ACE and ACE2. Additionally, these data suggest a role for ACE-expressing myeloid cells in the pathogenesis of radiation pneumonitis. Finally, the observed sex-differences underscore the need for consideration of sex as a biological variable in the development of medical countermeasures for radiation exposure.
在实验动物模型中，正常组织辐射损伤的表现和严重程度存在生物学性别差异，这已得到充分记录。此前我们证明，雄性和雌性大鼠对高剂量局部身体照射（PBI）有不同且高度可重复的反应，雄性大鼠比雌性大鼠对胃肠道急性辐射综合征（GI-ARS）和放射性肺炎更敏感。在本研究中，我们调查了肾素-血管紧张素系统（RAS）酶血管紧张素转换酶（ACE）和ACE2的差异表达是否导致了观察到的辐射反应中的性别相关差异。在症状性肺炎期间，仅雄性大鼠的全肺中ACE与ACE2（ACE/ACE2）蛋白的相对比例因辐射而显著增加。用小分子ACE2激动剂乙酰氨基阿维菌素（DIZE）进行全身治疗可增加肺ACE2活性，并降低两性放射性肺炎期间的发病率。值得注意的是，DIZE治疗还消除了雄性大鼠在GI-ARS期间的发病率。然后，我们评估了受辐射的骨髓（BM）区室对肺炎期间肺免疫细胞浸润和ACE失衡的影响。与未受辐射的供体相比，移植受辐射供体的骨髓会增加肺炎期间肺中表达ACE的髓样细胞浸润和免疫ACE活性。总之，这些数据表明辐射会诱导肾素-血管紧张素系统酶ACE和ACE2出现性别依赖性失衡。此外，这些数据表明表达ACE的髓样细胞在放射性肺炎的发病机制中起作用。最后，观察到的性别差异强调了在制定辐射暴露医学对策时需要将性别作为一个生物学变量加以考虑。
