McGovern John, Perry Carrighan, Ghincea Alexander, Herzog Erica L, Shao Shuai, Sun Huanxing
Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States.
Department of Molecular Medicine/Experimental Pathology, Yale School of Medicine, New Haven, Connecticut, United States.
Am J Physiol Lung Cell Mol Physiol. 2025 Jan 1;328(1):L15-L29. doi: 10.1152/ajplung.00062.2024. Epub 2024 Oct 29.
Progressive lung fibrosis is often fatal and has limited treatment options. Though the mechanisms are poorly understood, fibrosis is increasingly linked with catecholamines such as adrenaline (AD) and noradrenaline (NA) and hormones such as aldosterone (ALD). The essential functions of the adrenal glands include the production of catecholamines and numerous hormones, but the contribution of adrenal glands to lung fibrosis remains less well studied. Here, we characterized the impact of surgical adrenal ablation in the bleomycin model of lung fibrosis. Wild-type mice underwent surgical adrenalectomy or sham surgery followed by bleomycin administration. We found that although bleomycin-induced collagen overdeposition in the lung was not affected by adrenalectomy, histologic indices of lung remodeling were ameliorated. These findings were accompanied by a decrease of lymphocytes in bronchoalveolar lavage (BAL) and macrophages in lung tissues, along with concomitant reductions in alpha-smooth muscle actin (αSMA) and fibronectin. Surgical adrenalectomy completely abrogated AD, not NA, detection in all compartments. Systemic ALD levels were reduced after adrenalectomy, whereas ALD levels in lung tissues remained unaffected. Taken together, these results support the presence of a pulmonary-adrenal axis in lung fibrosis and suggest that adrenalectomy is protective in this disease. Further investigation will be needed to better understand this observation and aid in the development of novel therapeutic strategies. The lung-adrenal axis plays a significant role in pulmonary fibrosis. Adrenalectomy provides protection against lung fibrotic ECM remodeling and lung inflammation by reducing the levels of lymphocytes in BAL and macrophages in lung of bleomycin-treated mice. Although compared with sham surgery, adrenalectomy raised collagen concentration in uninjured mice, there was no discernible difference in bleomycin-induced collagen accumulation. However, adrenalectomy significantly reversed the enhanced expression and colocalization of αSMA and fibronectin induced by bleomycin.
进行性肺纤维化通常是致命的，治疗选择有限。尽管其机制尚不清楚，但纤维化与儿茶酚胺如肾上腺素（AD）和去甲肾上腺素（NA）以及激素如醛固酮（ALD）的联系日益密切。肾上腺的基本功能包括儿茶酚胺和多种激素的产生，但肾上腺对肺纤维化的贡献仍研究较少。在此，我们在博来霉素诱导的肺纤维化模型中，对手术切除肾上腺的影响进行了表征。野生型小鼠接受手术去肾上腺或假手术，随后给予博来霉素。我们发现，尽管博来霉素诱导的肺中胶原蛋白过度沉积不受去肾上腺的影响，但肺重塑的组织学指标有所改善。这些发现伴随着支气管肺泡灌洗（BAL）中淋巴细胞和肺组织中巨噬细胞的减少，同时α平滑肌肌动蛋白（αSMA）和纤连蛋白也减少。手术去肾上腺完全消除了所有组织中AD的检测，但未消除NA的检测。去肾上腺后全身ALD水平降低，而肺组织中的ALD水平不受影响。综上所述，这些结果支持肺纤维化中存在肺 - 肾上腺轴，并表明去肾上腺在这种疾病中具有保护作用。需要进一步研究以更好地理解这一观察结果，并有助于开发新的治疗策略。肺 - 肾上腺轴在肺纤维化中起重要作用。去肾上腺通过降低博来霉素处理小鼠BAL中的淋巴细胞水平和肺中的巨噬细胞水平，为肺纤维化的细胞外基质重塑和肺部炎症提供保护。尽管与假手术相比，去肾上腺使未受伤小鼠的胶原蛋白浓度升高，但在博来霉素诱导的胶原蛋白积累方面没有明显差异。然而，去肾上腺显著逆转了博来霉素诱导的αSMA和纤连蛋白的表达增强及共定位。
