Partial inhibition of integrin αvβ6 prevents pulmonary fibrosis without exacerbating inflammation
Partial inhibition of integrin αvβ6 prevents pulmonary fibrosis without exacerbating inflammation
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DOI：
10.1164/rccm.200706-805oc
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发表时间：
2008-01-01
影响因子：
24.7
通讯作者：
Violette, Shelia M.
中科院分区：
文献类型：
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作者：
Horan, Gerald S.;Wood, Susan;Violette, Shelia M.
转化生长因子(TGF)-β在许多肺纤维化的病理过程中起核心作用。抑制肺组织中转化生长因子β的关键激活剂整合素αvβ6是一种有吸引力的治疗策略，因为有可能在不影响转化生长因子-β6的其他稳态作用的情况下抑制αvβ6上调部位的转化生长因子-β6。目的：分析人肺纤维化中αvβ6的表达，并从功能上检验在博莱霉素诱导的小鼠肺纤维化中抑制αvβ6介导的转化生长因子-β6激活的疗效。在博莱霉素诱导的小鼠肺纤维化中，评价了阻断αvβ6介导的转化生长因子-β6激活的单抗浓度范围。测量和主要结果：αvβ6是肺泡管和肺泡内衬里的肺泡细胞过度表达的人类肺纤维化。在博莱霉素模型中，αvβ6抗体能有效地阻断肺纤维化。在高剂量时，炎症标志物和巨噬细胞活化的表达增加，这与肺组织中转化生长因子-β的抑制作用一致。低剂量的抗体可在不增加肺泡炎性细胞或巨噬细胞活化标志物的情况下减弱胶原的表达。结论：使用αvβ6整合素抗体部分抑制转化生长因子-β能有效地阻断小鼠肺纤维化而不加重炎症。此外，纤维化细胞因子转化生长因子-β的激活剂αvβ6在人肺纤维化中的表达升高，提示αvβ6单抗有望成为治疗肺纤维化的一种新的治疗策略。
Rationale Transforming growth factor (TGF)-beta has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin alpha v beta 6, a key activator of TGF-beta in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF-beta at sites of alpha v beta 6 up-regulation without affecting other homeostatic roles of TGF-beta.Objectives: To analyze the expression of alpha v beta 6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of alpha v beta 6-mediated TGF-beta activation in murine bleomycin-induced pulmonary fibrosis.Methods: Lung biopsies from patients with a diagnosis of systemic sclerosis or idiopathic pulmonary fibrosis were stained for alpha v beta 6 expression. A range of concentrations of a monoclonal antibody that blocks alpha v beta 6-mediated TGF-beta activation was evaluated in murine bleomycin-induced lung fibrosis.Measurements and Main Results: alpha v beta 6 is overexpressed inhuman lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, alpha v beta 6 antibody was effective in blocking pulmonary fibrosis. At high doses, there was increased expression of markers of inflammation and macrophage activation, consistent with the effects of TGF-beta inhibition in the lung. Low doses of antibody attenuated Collagen expression without increasing alveolar inflammatory cell populations or macrophage activation markers.Conclusions: Partial inhibition of TGF-beta using alpha v beta 6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of alpha v beta 6, an activator of the fibrogenic cytokine, TGF-beta, in human pulmonary fibrosis suggests that alpha v beta 6 monoclonal antibodies could represent a promising new therapeutic strategy for treating pulmonary fibrosis.