Botney M D, Bahadori L, Gold L I
Respiratory and Critical Care Division, Jewish Hospital, Washington University Medical Center, St. Louis, MO 63110.
Am J Pathol. 1994 Feb;144(2):286-95.
Active exogenous transforming growth factor-beta s (TGF-beta s) are potent modulators of extracellular matrix synthesis in cell culture and stimulate matrix synthesis in wounds and other remodeling tissues. The role of endogenous TGF-beta s in remodeling tissues is less well defined. Vascular remodeling in the pulmonary arteries of patients with primary pulmonary hypertension is characterized, in part, by abnormal deposition of immunohistochemically detectable procollagen, thereby identifying actively remodeling vessels. We used this marker of active matrix synthesis to begin defining the in vivo role of TGF-beta in the complex milieu of actively remodeling tissues. Immunohistochemistry using isoform-specific anti-TGF-beta antibodies was performed to determine whether TGF-beta was present in actively remodeling hypertensive pulmonary arteries 20 to 500 microns in diameter. Intense, cell-associated TGF-beta 3 immunoreactivity was observed in the media and neointima of these hypertensive muscular arteries. Immunostaining was present, but less intense, in normal arteries of comparable size. TGF-beta 2 immunoreactivity was observed in normal vessels and was increased slightly in hypertensive vessels, in a pattern resembling TGF-beta 3 immunoreactivity. No staining was associated with the adventitia. TGF-beta 1 immunostaining was either faint or absent in both normal and hypertensive vessels. Comparison of procollagen and TGF-beta localization demonstrated that TGF-beta 2 and TGF-beta 3 colocalized at all sites of procollagen synthesis. However, TGF-beta was observed in vessels, or vascular compartments, where there was no procollagen synthesis. Procollagen immunoreactivity was not present in normal vessels that showed immunoreactivity for TGF-beta 2 and TGF-beta 3. These observations suggest: a) the stimulation of procollagen synthesis by TGF-beta in vivo is more complex than suggested by in vitro studies and b) a potential role for TGF-beta 2 or TGF-beta 3, but not TGF-beta 1, in hypertensive pulmonary vascular remodeling.
活性外源性转化生长因子-β（TGF-β）在细胞培养中是细胞外基质合成的有效调节剂，并能刺激伤口及其他重塑组织中的基质合成。内源性TGF-β在重塑组织中的作用尚不太明确。原发性肺动脉高压患者的肺动脉血管重塑部分特征为免疫组织化学可检测到的前胶原异常沉积，从而确定了处于活跃重塑状态的血管。我们利用这种活性基质合成标志物来开始确定TGF-β在活跃重塑组织的复杂环境中的体内作用。使用亚型特异性抗TGF-β抗体进行免疫组织化学，以确定直径为20至500微米的活跃重塑的高血压肺动脉中是否存在TGF-β。在这些高血压肌性动脉的中膜和内膜中观察到强烈的、与细胞相关的TGF-β3免疫反应性。在大小相当的正常动脉中也有免疫染色，但强度较低。在正常血管中观察到TGF-β2免疫反应性，在高血压血管中略有增加，其模式类似于TGF-β3免疫反应性。外膜未出现染色。在正常和高血压血管中，TGF-β1免疫染色均微弱或缺失。前胶原和TGF-β定位的比较表明，TGF-β2和TGF-β3在所有前胶原合成部位共定位。然而，在没有前胶原合成的血管或血管腔室中也观察到了TGF-β。对TGF-β2和TGF-β3呈免疫反应性的正常血管中不存在前胶原免疫反应性。这些观察结果表明：a）TGF-β在体内对前胶原合成的刺激比体外研究所显示的更为复杂；b）TGF-β2或TGF-β3，但不是TGF-β1，在高血压肺血管重塑中可能发挥作用。
