Akaishi Satoshi, Ogawa Rei, Hyakusoku Hiko
Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School Hospital, 1-1-5 Sendagi Bunkyo-ku, Tokyo, Japan.
Med Hypotheses. 2008;71(1):32-8. doi: 10.1016/j.mehy.2008.01.032. Epub 2008 Apr 11.
The mechanisms of fibroproliferation disease (FPD) of the skin, such as keloids and hypertrophic scars, are still unknown. Since mechanical stress appears to be an important factor for FPD generation, we have studied the intervening factors that connect mechanical stress with keloid and scar formation. Hence, we introduce our "neurogenic inflammation hypothesis" in this paper. Our hypothesis is as follows. Mechanical stress, including skin stretching, stimulates mechanosensitive nociceptors on sensory fibers in the skin. Stimulated fibers release neuropeptides, including SP and CGRP, and these peptides bind to the receptors SP-NK1R and CGRP-CGRP1R on various cells in the skin. Moreover, histamine release is upregulated by mast cells. Consequently, activated endothelial cells and vascular smooth muscle cells induce vasodilation and permeabilization of vessels. Cytokine production, including TGFbeta and NGF, is also stimulated by various cells. The neurogenic inflammation and upregulation of TGFbeta would activate fibroblasts through various signals. Interestingly, overexpressed NGF may induce the hyper-release of neuropeptides from sensory fibers, resulting in the accumulation of neuropeptides even in the absence of mechanical stress, once the malignant cycle has started. Moreover, individual differences in FPD generation may be based on differences in reactivity towards neuropeptides, NGF, and other neurotrophins. Hence, neuropeptide antagonists may be effective against FPD. While further experimental studies and clinical confirmation are needed, our hypothesis may provide new insights into the etiology and pathology of FPD of the skin, such as keloids and hypertrophic scars.
皮肤纤维增生性疾病（FPD），如瘢痕疙瘩和增生性瘢痕，其发病机制尚不清楚。由于机械应力似乎是FPD发生的一个重要因素，我们研究了将机械应力与瘢痕疙瘩和瘢痕形成联系起来的干预因素。因此，我们在本文中提出了“神经源性炎症假说”。我们的假说如下。机械应力，包括皮肤拉伸，刺激皮肤感觉纤维上的机械敏感伤害感受器。受刺激的纤维释放神经肽，包括P物质（SP）和降钙素基因相关肽（CGRP），这些肽与皮肤上各种细胞上的P物质受体NK1R和CGRP受体CGRP1R结合。此外，肥大细胞上调组胺释放。因此，活化的内皮细胞和血管平滑肌细胞诱导血管舒张和血管通透性增加。各种细胞也刺激包括转化生长因子β（TGFβ）和神经生长因子（NGF）在内的细胞因子产生。神经源性炎症和TGFβ的上调会通过各种信号激活成纤维细胞。有趣的是，一旦恶性周期开始，过度表达的NGF可能会诱导感觉纤维过度释放神经肽，导致即使在没有机械应力的情况下神经肽也会积累。此外，FPD发生的个体差异可能基于对神经肽、NGF和其他神经营养因子反应性的差异。因此，神经肽拮抗剂可能对FPD有效。虽然还需要进一步的实验研究和临床证实，但我们的假说可能为皮肤FPD，如瘢痕疙瘩和增生性瘢痕的病因学和病理学提供新的见解。
