Woods Parker S, Tazi Mia F, Chesarino Nicholas M, Amer Amal O, Davis Ian C
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio;
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio.
Am J Physiol Lung Cell Mol Physiol. 2015 Jun 1;308(11):L1136-44. doi: 10.1152/ajplung.00078.2015. Epub 2015 Apr 3.
As the eighth leading cause of annual mortality in the USA, influenza A viruses are a major public health concern. In 20% of patients, severe influenza progresses to acute lung injury (ALI). However, pathophysiological mechanisms underlying ALI development are poorly defined. We reported that, unlike wild-type (WT) C57BL/6 controls, influenza A virus-infected mice that are heterozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (HETs) did not develop ALI. This effect was associated with higher IL-6 and alveolar macrophages (AMs) at 6 days postinfection (d.p.i.) in HET bronchoalveolar lavage fluid (BALF). In the present study, we found that HET AMs were an important source of IL-6 at 6 d.p.i. Infection also induced TGF-β production by HET but not WT mice at 2 d.p.i. TGF-β neutralization at 2 d.p.i. (TGF-N) significantly reduced BALF IL-6 in HETs at 6 d.p.i. Neither TGF-N nor IL-6 neutralization at 4 d.p.i. (IL-6-N) altered postinfection weight loss or viral replication in either mouse strain. However, both treatments increased influenza A virus-induced hypoxemia, pulmonary edema, and lung dysfunction in HETs to WT levels at 6 d.p.i. TGF-N and IL-6-N did not affect BALF AM and neutrophil numbers but attenuated the CXCL-1/keratinocyte chemokine response in both strains and reduced IFN-γ production in WT mice. Finally, bone marrow transfer experiments showed that HET stromal and myeloid cells are both required for protection from ALI in HETs. These findings indicate that TGF-β-dependent production of IL-6 by AMs later in infection prevents ALI development in influenza A virus-infected HET mice.
作为美国年度死亡率的第八大主要原因，甲型流感病毒是一个重大的公共卫生问题。在20%的患者中，严重流感会发展为急性肺损伤（ALI）。然而，ALI发生的病理生理机制尚不清楚。我们报道，与野生型（WT）C57BL/6对照不同，囊性纤维化跨膜传导调节因子F508del突变杂合的甲型流感病毒感染小鼠（HETs）不会发生ALI。这种效应与感染后6天（d.p.i.）HET支气管肺泡灌洗液（BALF）中较高的IL-6和肺泡巨噬细胞（AMs）有关。在本研究中，我们发现HET AMs是感染后6天IL-6的重要来源。感染还在感染后2天诱导HET而非WT小鼠产生TGF-β。在感染后2天进行TGF-β中和（TGF-N）可显著降低感染后6天HETs的BALF IL-6。在感染后4天进行TGF-N或IL-6中和（IL-6-N）均未改变两种小鼠品系感染后的体重减轻或病毒复制。然而，两种处理均使感染后6天HETs中甲型流感病毒诱导的低氧血症、肺水肿和肺功能障碍增加至WT水平。TGF-N和IL-6-N不影响BALF AM和中性粒细胞数量，但减弱了两种品系的CXCL-1/角质形成细胞趋化因子反应，并降低了WT小鼠的IFN-γ产生。最后，骨髓移植实验表明，HET基质细胞和髓样细胞对于HETs免受ALI的保护均是必需的。这些发现表明，感染后期AMs依赖TGF-β产生IL-6可防止甲型流感病毒感染的HET小鼠发生ALI。
