Ding Kathy L, Smith Caroline, Seedorf Gregory, Abman Steven H
Medical Student Research Track, University of Colorado School of Medicine, Aurora, CO, USA.
Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
Pediatr Res. 2024 Oct 11. doi: 10.1038/s41390-024-03562-0.
Bronchopulmonary dysplasia (BPD), the chronic lung disease associated with prematurity, is characterized by poor alveolar and vascular growth, interstitial fibrosis, and pulmonary hypertension (PH). Although multifactorial in origin, the pathophysiology of BPD is partly attributed to hyperoxia-induced postnatal injury, resulting in lung fibrosis. Recent work has shown that anti-fibrotic agents, including Nintedanib (NTD), can preserve lung function in adults with idiopathic pulmonary fibrosis. However, NTD is a non-specific tyrosine kinase receptor inhibitor that can potentially have adverse effects on the developing lung, and whether NTD treatment can prevent or worsen risk for BPD and PH is unknown.
We hypothesize that NTD treatment will preserve lung growth and function and prevent PH in an experimental model of hyperoxia-induced BPD in rats.
Newborn rats were exposed to either hyperoxia (90%) or room air (RA) conditions and received daily treatment of NTD or saline (control) by intraperitoneal (IP) injections (1 mg/kg) for 14 days, beginning on postnatal day 1. At day 14, lung mechanics were measured prior to harvesting lung and cardiac tissue. Lung mechanics, including total respiratory resistance and compliance, were measured using a flexiVent system. Lung tissue was evaluated for radial alveolar counts (RAC), mean linear intercept (MLI), pulmonary vessel density (PVD), and pulmonary vessel wall thickness (PVWT). Right ventricular hypertrophy (RVH) was quantified with cardiac weights using Fulton's index (ratio of right ventricle to the left ventricle plus septum).
When compared with RA controls, hyperoxia exposure reduced RAC by 64% (p < 0.01) and PVD by 65% (p < 0.01) and increased MLI by 108% (p < 0.01) and RVH by 118% (p < 0.01). Hyperoxia increased total respiratory resistance by 94% and reduced lung compliance by 75% (p < 0.01 for each). NTD administration restored RAC, MLI, RVH, PVWT and total respiratory resistance to control values and improved PVD and total lung compliance in the hyperoxia-exposed rats. NTD treatment of control animals did not have adverse effects on lung structure or function at 1 mg/kg. When administered at higher doses of 50 mg/kg, NTD significantly reduced alveolar growth in RA controls, suggesting dose-related effects on normal lung structure.
We found that NTD treatment preserved lung alveolar and vascular growth, improved lung function, and reduced RVH in experimental BPD in infant rats without apparent adverse effects in control animals. We speculate that although potentially harmful at high doses, NTD may provide a novel therapeutic strategy for prevention of BPD and PH.
Anti-fibrotic therapies may be a novel therapeutic strategy for the treatment or prevention of BPD. High-dose anti-fibrotics may have adverse effects on developing lungs, while low-dose anti-fibrotics may treat or prevent BPD. There is very little preclinical and clinical data on the use of anti-fibrotics in the developing lung. Dose timing and duration of anti-fibrotic therapies may be critical for the treatment of neonatal lung disease. Currently, strategies for the prevention and treatment of BPD are lacking, especially in the context of lung fibrosis, so this research has major clinical applicability.
支气管肺发育不良（BPD）是一种与早产相关的慢性肺部疾病，其特征为肺泡和血管生长不良、间质纤维化以及肺动脉高压（PH）。尽管其病因是多因素的，但BPD的病理生理学部分归因于高氧诱导的产后损伤，从而导致肺纤维化。最近的研究表明，包括尼达尼布（NTD）在内的抗纤维化药物可在特发性肺纤维化成年患者中保留肺功能。然而，NTD是一种非特异性酪氨酸激酶受体抑制剂，可能对发育中的肺产生潜在不良影响，且NTD治疗能否预防或加重BPD和PH的风险尚不清楚。
我们假设在大鼠高氧诱导的BPD实验模型中，NTD治疗将保留肺生长和功能并预防PH。
新生大鼠暴露于高氧（90%）或室内空气（RA）环境，并从出生后第1天开始，通过腹腔内（IP）注射（1mg/kg）每日接受NTD或生理盐水（对照）治疗，持续14天。在第14天，在收获肺和心脏组织之前测量肺力学。使用flexiVent系统测量肺力学，包括总呼吸阻力和顺应性。评估肺组织的径向肺泡计数（RAC）、平均线性截距（MLI）、肺血管密度（PVD）和肺血管壁厚度（PVWT）。使用富尔顿指数（右心室与左心室加室间隔的比值）通过心脏重量对右心室肥厚（RVH）进行量化。
与RA对照组相比，高氧暴露使RAC降低64%（p<0.01），PVD降低65%（p<0.01），MLI增加108%（p<0.01），RVH增加118%（p<0.01）。高氧使总呼吸阻力增加94%，肺顺应性降低75%（每项p<0.01）。给予NTD可使高氧暴露大鼠的RAC、MLI、RVH、PVWT和总呼吸阻力恢复至对照值，并改善PVD和总肺顺应性。以1mg/kg剂量对对照动物进行NTD治疗对肺结构或功能没有不良影响。当以50mg/kg的更高剂量给药时，NTD显著降低了RA对照组的肺泡生长，表明对正常肺结构有剂量相关效应。
我们发现，NTD治疗可保留幼鼠实验性BPD中的肺泡和血管生长，改善肺功能，并降低RVH，且对对照动物无明显不良影响。我们推测，尽管高剂量时可能有害，但NTD可能为预防BPD和PH提供一种新的治疗策略。
抗纤维化疗法可能是治疗或预防BPD的一种新的治疗策略。高剂量抗纤维化药物可能对发育中的肺有不良影响，而低剂量抗纤维化药物可能治疗或预防BPD。关于在发育中的肺中使用抗纤维化药物的临床前和临床数据非常少。抗纤维化疗法的剂量时机和持续时间可能对新生儿肺部疾病的治疗至关重要。目前，缺乏预防和治疗BPD的策略，尤其是在肺纤维化的情况下，因此本研究具有重要的临床适用性。
