Four full-thickness skin wounds made in normal mice led to the significant increase in levels of nerve growth factor (NGF) in sera and in wounded skin tissues. Since sialoadenectomy before the wounds inhibited the rise in serum levels of NGF, the NGF may be released from the salivary gland into the blood stream after the wounds. In contrast, the fact that messenger RNA and protein of NGF were detected in newly formed epithelial cells at the edge of the wound and fibroblasts consistent with the granulation tissue produced in the wound space, suggests that NGF was also produced at the wounded skin site. Topical application of NGF into the wounds accelerated the rate of wound healing in normal mice and in healing-impaired diabetic KK/Ta mice. This clinical effect of NGF was evaluated by histological examination; the increases in the degree of reepithelialization, the thickness of the granulation tissue, and the density of extracellular matrix were observed. NGF also increased the breaking strength of healing linear wounds in normal and diabetic mice. These findings suggested that NGF immediately and constitutively released in response to cutaneous injury may contribute to wound healing through broader biological activities, and NGF improved the diabetic impaired response of wound healing.

IntroductionGain-of-function mutations in the c-kit receptor induce factorindependent proliferation of mast cells, thereby resulting in neoplastic transformation. 1 Various c-kit receptor mutations have been identified in different mast cell lines that have an ability to proliferate in the absence of any growth factor. 2-6 HMC-1 cells, which were derived from human mast cell leukemia, have 2 point mutations in the intracellular juxtamembrane domain (Val560Gly) and in the catalytic domain (Asp816Val) of the c-kit receptor. 2,6 The former mutation was also found in the c-kit receptor in cells from gastrointestinal stromal tumor (GIST), and the latter is known to exist most commonly in cells from human mastocytosis. 7,8 Because of these mutations, the tyrosine kinase of the c-kit receptor is automatically phosphorylated, and the related growth signal is activated. Several signaling molecules have been identified as candidates for transducing c-kit receptor signals, including mitogenactivated protein (MAP) kinase, phosphatidylinositol 3 (PI3) kinase, protein kinase C (PKC), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. [9][10][11] Recently available tyrosine kinase inhibitors have been applied to c-kit-dependent diseases, including GIST and mastocytosis; however, therapeutic effects have been limited in the treatment of mastocytosis in contrast to the great success in the treatment of GIST. [12][13][14] Mutational analysis has revealed some variants of the c-kit gene in patients with mastocytosis. Imatinib mesylate (STI571) was shown to be effective against mast cell diseases involving wild-type c-kit and mutants with Val560Gly or Phe522Cys substitutions. 14,15 However, STI571 was not effective against aggressive systemic mastocytosis involving an Asp816Val mutation in the c-kit receptor. 15 Homeostatic or nonhomeostatic cell renewal is controlled through cell cycle progression. Entry into the S phase normally relies on mitogenic stimulation, involving growth factors, and is regulated by cell cycle regulatory molecules, such as cyclins, cyclin-dependent kinases (CDKs), and a retinoblastoma protein (pRb). 16,17 D-type cyclins, namely cyclin D 1 , D 2 , and D 3 , are growth factor sensitive, and their expression is facilitated in response to growth factor stimulation. Byl binding with CDK4 and CDK6, D-type cyclins control a kinase activity of CDK and phosphorylate substrates that are required for G 1 progression and S phase entry. [18][19][20] One of their important targets is pRb. [18][19][20] We have already reported that the expression of cyclin D 3 and the phosphorylation of pRb are accelerated in mouse bone marrow-derived cultured mast cells (BMCMCs) incubated with stem cell factor (SCF), indicating that these regulatory molecules are essential for cell cycle progression in mast cell proliferation. 21 NF-B, a dimeric transcription factor of the rel family, exists as an inactive form in the cytoplasm by binding its endogenous Materials and methods Cell cultureHMC-1 cel...

Elevated skin surface pH has been reported in patients with atopic dermatitis (AD). Here we explored the role of skin pH in the pathogenesis of AD using the NC/Tnd murine AD model. Alkalinization of the skin of asymptomatic NC/Tnd mice housed in specific pathogen-free (SPF) conditions induced KLK5 and activated the protease-activated receptor 2 (PAR2), resulting in thymic stromal lymphopoietin (TSLP) secretion and a cutaneous T-helper 2 allergic response. This was associated with increased trans-epidermal water loss and development of eczematous lesions in these SPF NC/Tnd mice, which normally do not suffer from AD. Injection of recombinant TSLP also induced scratching behavior in the SPF NC/Tnd mice. TSLP production and dermatitis induced by alkalinization of the skin could be blocked by the PAR2 antagonist ENMD-1068. In contrast, weak acidification of eczematous skin in conventionally housed NC/Tnd mice reduced kallikrein (KLK) 5　activity and ameliorated the dermatitis. Onset of the dermatitis was associated with increased epidermal filaggrin expression and impaired activity of the sodium/hydrogen exchanger NHE1, a known regulator of skin pH. We conclude that alterations in skin pH directly modulate KLK5 activity leading to skin barrier dysfunction, itch, and dermatitis via the PAR2-TSLP pathway.Journal of Investigative Dermatology accepted article preview online, 22 September 2015. doi:10.1038/jid.2015.363.

These findings suggest that some components of heat-treated L. GG may have an ability to delay the onset and suppress the development of atopic dermatitis, probably through a strong induction of IL-10 in intestinal lymphoid organs and systemic levels.