P3: Infrared Irradiation and Scleroderma Skin

皮肤中过度的胶原蛋白沉积是硬皮病的标志。目前没有安全和/或 有效的治疗。过度积累的胶原蛋白是负责显着增厚和硬 对硬皮病的受累皮肤有感觉。因此，可以安全地增强胶原蛋白分解的疗法 我们已经积累了确凿的证据，表明紫外线照射人体皮肤会激活一种 细胞中复杂的信号级联，最终导致基质的量增加数倍， 金属蛋白酶（MMPs），随之降解胶原蛋白，同时抑制新的 前胶原合成。因此，通过去除已经存在的真皮胶原蛋白并抑制 新的胶原蛋白，紫外线是能够造成净胶原蛋白损失在人类皮肤。作为一种光疗设备 然而，UVB（290- 320 nm）和UVA 1（340- 400 nm）都具有显著局限性。更有活力的UVB 与晒伤反应有关，其致癌潜力已得到充分证实。UVA 1更安全， 人体皮肤更容易耐受。然而，我们已经了解到，无论是自然的和紫外线诱导的皮肤 色素沉着是UVA 1的有效阻断剂。硬皮病影响所有皮肤层次的受试者 色素沉着（I-VI型）。一种不受肤色影响的抗纤维化治疗方式将提供 医学上的重大进步，尤其是在深色肤色的非裔美国人、西班牙人、印度人或亚洲人中 患者（V型和VI型）。我们的初步数据表明，红外辐射（IR;特别是700-4，000 nm） 将皮肤表面温度提高到41摄氏度，能够安全地诱导MMPs并抑制前胶原 与人类皮肤色素无关。因此，我们假设IR也会改善硬皮病， 其他纤维化疾病。我们建议1）充分表征IR减少正常皮肤中胶原蛋白的能力， 2）获得IR对硬皮病皮肤作用的初步数据。协助生成的数据 的RDCC将构成向NIH申请资助一项多中心IR治疗试验的基础， 硬皮病

Excessive collagen deposition in the skin is a hallmark of scleroderma. Currently there are no safe and/or effective therapies. Excessive accumulation of collagen is responsible for the markedly thickened and hard feel to the involved skin of scleroderma. Therefore, a therapy that can safely enhance collagen breakdown is expected to improve it. We have accumulated solid evidence that UV irradiation of human skin activates a complex signaling cascade in cells that ultimately results in a several fold increase in the amount of matrix metalloproteinases (MMPs) with consequent degradation of collagen, while simultaneously inhibiting new procollagen synthesis. Thus, by removing already present dermal collagen and suppressing production of new collagen, UV is capable of causing a net collagen loss in human skin. As a phototherapeutic device however, both UVB (290-320nm) and UVA1 (340-400nm) have significant limitations. More energetic UVB is associated with sunburn reaction, and its carcinogenic potential is well established. UVA1 is safer and better tolerated by human skin. However, we have learned that both natural and UV-induced skin pigmentation are effective blockers of UVA1. Scleroderma affects subjects with all levels of skin pigmentation (types I-VI). An antifibrotic treatment modality that is not influenced by skin color will offer a significant medical advancement, especially in darkly pigmented African American, Hispanic, Indian, or Asian patients (types V&VI). Our preliminary data indicate that infrared irradiation (IR; specifically 700-4,000nm) that raises skin surface temperature to 41 degrees C is capable of safely inducing MMPs and inhibiting procollagen irrespective of human skin pigmentation. Thus we hypothesize that IR will also improve scleroderma and other fibrotic diseases. We propose to 1) fully characterize the ability of IR to reduce collagen in normal skin, and 2) obtain preliminary data of the IR effect on scleroderma skin. The data generated with the assistance of RDCC will form the basis for an application to the NIH to fund a multicenter IR therapeutic trial in scleroderma.