da Silva A L, Magalhães R F, Branco V C, Silva J D, Cruz F F, Marques P S, Ferreira T P T, Morales M M, Martins M A, Olsen P C, Rocco P R M
Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
Br J Pharmacol. 2016 Apr;173(7):1236-47. doi: 10.1111/bph.13430. Epub 2016 Feb 25.
Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in understanding of its pathophysiology, asthma remains a major public health problem, and new therapeutic strategies are urgently needed. In this context, we sought to ascertain whether treatment with the TK inhibitor dasatinib might repair inflammatory and remodelling processes, thus improving lung function, in a murine model of asthma.
Animals were sensitized and subsequently challenged, with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, animals were treated with dasatinib, dexamethasone, or saline, every 12 h for 7 consecutive days. Twenty-four hours after the last treatment, the animals were killed, and data were collected. Lung structure and remodelling were evaluated by morphometric analysis, immunohistochemistry, and transmission electron microscopy of lung sections. Inflammation was assessed by cytometric analysis and ELISA, and lung function was evaluated by invasive whole-body plethysmography.
In OVA mice, dasatinib, and dexamethasone led to significant reductions in airway hyperresponsiveness. Dasatinib was also able to attenuate alveolar collapse, contraction index, and collagen fibre deposition, as well as increasing elastic fibre content, in OVA mice. Concerning the inflammatory process, dasatinib reduced inflammatory cell influx to the airway and lung-draining mediastinal lymph nodes, without inducing the thymic atrophy promoted by dexamethasone.
In this model of allergic asthma, dasatinib effectively blunted the inflammatory and remodelling processes in asthmatic lungs, enhancing airway repair and thus improving lung mechanics.
哮喘的特征为慢性肺部炎症和气道高反应性。尽管在其病理生理学理解方面取得了最新进展，但哮喘仍然是一个主要的公共卫生问题，迫切需要新的治疗策略。在此背景下，我们试图确定在哮喘小鼠模型中，用酪氨酸激酶（TK）抑制剂达沙替尼进行治疗是否可以修复炎症和重塑过程，从而改善肺功能。
用卵清蛋白（OVA）或生理盐水使动物致敏，随后进行激发。在最后一次激发后24小时，动物分别接受达沙替尼、地塞米松或生理盐水治疗，每12小时给药一次，连续7天。在最后一次治疗后24小时，处死动物并收集数据。通过形态计量分析、免疫组织化学和肺切片的透射电子显微镜评估肺结构和重塑。通过细胞计数分析和酶联免疫吸附测定（ELISA）评估炎症，并通过侵入性全身体积描记法评估肺功能。
在OVA小鼠中，达沙替尼和地塞米松可显著降低气道高反应性。达沙替尼还能够减轻OVA小鼠的肺泡萎陷、收缩指数和胶原纤维沉积，同时增加弹性纤维含量。关于炎症过程，达沙替尼减少了炎症细胞流入气道和引流肺的纵隔淋巴结，而不会诱发地塞米松所促进的胸腺萎缩。
在该过敏性哮喘模型中，达沙替尼有效地抑制了哮喘肺部的炎症和重塑过程，增强了气道修复，从而改善了肺力学。
