The role of substance P in the pathogenesis of pterygia.

PURPOSE Pterygium is a prevalent ocular surface disorder thought to be triggered by chronic ultraviolet damage to the limbus. One of the enigmatic features of pterygium is its wing-like shape, and the mechanism(s) supporting its centripetal growth remain to be elucidated. Because the growth pattern of pterygia mirrors the radial arrangement of corneal nerves, the authors propose that neuropeptides may facilitate its directional growth. This hypothesis prompted an investigation of the role of the sensory neuropeptide substance P (SP) and its receptor (NK(1) receptor) in directing cell migration in pterygia that may explain the characteristic growth pattern. METHODS Immunohistochemical analysis for SP and the NK(1) receptor was performed on five pterygium specimens with corresponding autologous conjunctiva and limbus. Migration of pterygium epithelium, fibroblasts, and vascular endothelial cells toward SP was assessed by using a modified Boyden chamber. RESULTS SP and NK(1) receptors were localized to infiltrating fibroblasts, mononuclear cells and the epithelia of pterygium, conjunctiva, and limbus, with elevated NK(1) receptor staining observed in pterygia. SP at nanomolar concentrations induced cell migration in pterygium fibroblasts and vascular endothelium in a dose-dependent fashion, which was inhibited by an NK(1) receptor antagonist. Pterygium epithelial cells were not migratory in these experiments. CONCLUSIONS For the first time, this study showed the presence of NK(1) receptor in pterygia and that SP is a potent chemoattractant for pterygium fibroblasts and vascular endothelial cells, implying that SP may contribute to the shape of pterygia through its profibrogenic and angiogenic action.

[1]  A. J. Park,et al.  Endothelial progenitor cells in pterygium pathogenesis , 2007, Eye.

[2]  D. Wakefield,et al.  Epidermal growth factor receptor signaling is partially responsible for the increased matrix metalloproteinase-1 expression in ocular epithelial cells after UVB radiation. , 2005, The American journal of pathology.

[3]  M. Burdick,et al.  Broad-spectrum G protein-coupled receptor antagonist, [D-Arg1,D-Trp5,7,9,Leu11]SP: a dual inhibitor of growth and angiogenesis in pancreatic cancer. , 2005, Cancer research.

[4]  Sander R. Dubovy,et al.  Characterisation of myofibroblasts in fibrovascular tissues of primary and recurrent pterygia , 2005, British Journal of Ophthalmology.

[5]  A. Laslop,et al.  Secretoneurin in the peripheral ocular innervation. , 2005, Investigative ophthalmology & visual science.

[6]  J. Becker,et al.  A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increases peritoneal fibrinolytic activity , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Wakefield,et al.  Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metalloproteinases , 2004, Progress in Retinal and Eye Research.

[8]  C. Maggi,et al.  Tachykinins and tachykinin receptors: a growing family. , 2004, Life sciences.

[9]  A. Hopkins,et al.  Neurokinin‐1 receptor (NK‐1R) expression is induced in human colonic epithelial cells by proinflammatory cytokines and mediates proliferation in response to substance P , 2003, Journal of cellular physiology.

[10]  A. Kraneveld,et al.  Functional Expression of Neurokinin 1 Receptors on Mast Cells Induced by IL-4 and Stem Cell Factor1 , 2003, The Journal of Immunology.

[11]  T. Nishida,et al.  Restoration of corneal epithelial barrier function and wound healing by substance P and IGF-1 in rats with capsaicin-induced neurotrophic keratopathy. , 2003, Investigative ophthalmology & visual science.

[12]  D. Walsh,et al.  Enhancement of Angiogenesis by Endogenous Substance P Release and Neurokinin-1 Receptors During Neurogenic Inflammation , 2003, Journal of Pharmacology and Experimental Therapeutics.

[13]  F. Kruse,et al.  Corneal nerves: structure, contents and function. , 2003, Experimental eye research.

[14]  D. Wakefield,et al.  The role of ultraviolet irradiation and heparin-binding epidermal growth factor-like growth factor in the pathogenesis of pterygium. , 2003, The American journal of pathology.

[15]  J. Becker,et al.  Neurokinin-1 receptor and substance P messenger RNA levels increase during intraabdominal adhesion formation. , 2002, The Journal of surgical research.

[16]  Min Zhao,et al.  Electrical cues regulate the orientation and frequency of cell division and the rate of wound healing in vivo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  H. Kerl,et al.  Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats , 2002, Neuroscience Letters.

[18]  T. Nishida,et al.  Substance P and its metabolites in normal human tears. , 2002, Investigative ophthalmology & visual science.

[19]  Jianbo Wang,et al.  [Substance P up-regulates the TGF-beta 1 mRNA expression of human dermal fibroblasts in vitro]. , 2002, Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery.

[20]  Jun-Sub Choi,et al.  Expression of Vascular Endothelial Growth Factor and Inducible Nitric Oxide Synthase in Pterygia , 2001, Cornea.

[21]  B. Nelson,et al.  Perineural Invasion of Cutaneous Malignancies , 2001, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[22]  P. Chew,et al.  Vascular patterns in pterygium and conjunctival autografting: a pilot study using indocyanine green anterior segment angiography , 2001, The British journal of ophthalmology.

[23]  L. Urbán,et al.  Differential role of neurokinin receptors in human lymphocyte and monocyte chemotaxis , 2000, Regulatory Peptides.

[24]  D. Wakefield,et al.  Culture and characterisation of epithelial cells from human pterygia , 1999, The British journal of ophthalmology.

[25]  I. Chowers,et al.  Neurotrophic corneal endothelial failure complicating acute Horner syndrome. , 1999, Ophthalmology.

[26]  S. Kaufman,et al.  In vivo confocal imaging of corneal neovascularization. , 1998, Cornea.

[27]  W. Sekundo,et al.  Capillaries in the epithelium of pterygium , 1998, The British journal of ophthalmology.

[28]  A. Lambiase,et al.  Increased plasma levels of substance P in vernal keratoconjunctivitis. , 1997, Investigative ophthalmology & visual science.

[29]  C. Murphy,et al.  Synergistic effect of substance P with epidermal growth factor on epithelial migration in rabbit cornea. , 1997, Experimental eye research.

[30]  C. Murphy,et al.  Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1. , 1997, Archives of ophthalmology.

[31]  T. Chikama,et al.  The NK1 receptor and its participation in the synergistic enhancement of corneal epithelial migration by substance P and insulin‐like growth factor‐1 , 1997, British journal of pharmacology.

[32]  J. Polak,et al.  Innervation and neurokinin receptors during angiogenesis in the rat sponge granuloma , 1996, The Histochemical Journal.

[33]  T. Amemiya,et al.  Immunohistochemical localization of basic fibroblast growth factor, platelet derived growth factor, transforming growth factor-β and tumor necrosis factor-α in the pterygium , 1996 .

[34]  C. Wiedermann,et al.  Induction of endothelial cell differentiation into capillary-like structures by substance P. , 1996, European journal of pharmacology.

[35]  F. Gillardon,et al.  Calcitonin gene-related peptide, substance P and nitric oxide are involved in cutaneous inflammation following ultraviolet irradiation. , 1995, European journal of pharmacology.

[36]  R. Beuerman,et al.  Cell cycle kinetics in pterygium at three latitudes. , 1995, The British journal of ophthalmology.

[37]  C. Belmonte,et al.  Neurotrophic influences on corneal epithelial cells. , 1994, Experimental eye research.

[38]  S Amerini,et al.  Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. , 1994, The Journal of clinical investigation.

[39]  C. Swain,et al.  Identification of L-tryptophan derivatives with potent and selective antagonist activity at the NK1 receptor. , 1994, Journal of medicinal chemistry.

[40]  Y. Tano,et al.  Epithelial wound healing in the denervated cornea. , 1994, Current eye research.

[41]  C. Wiedermann,et al.  Stimulation of the chemotactic migration of human fibroblasts by substance P. , 1993, European journal of pharmacology.

[42]  M. Coroneo.  Pterygium as an early indicator of ultraviolet insolation: a hypothesis. , 1993, The British journal of ophthalmology.

[43]  C. Murphy,et al.  Stimulation of epithelial cell growth by the neuropeptide substance P , 1993, Journal of cellular biochemistry.

[44]  R. Swerlick,et al.  HMEC-1: establishment of an immortalized human microvascular endothelial cell line. , 1992, The Journal of investigative dermatology.

[45]  V. E. Pettorossi,et al.  Peripheral territory and neuropeptides of the trigeminal ganglion neurons centrally projecting through the oculomotor nerve demonstrated by fluorescent retrograde double-labeling combined with immunocytochemistry , 1991, Brain Research.

[46]  M. A. Pozo,et al.  Effects of capsaicin on corneal wound healing. , 1990, Investigative ophthalmology & visual science.

[47]  C. Maggi,et al.  Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. , 1990, Microvascular research.

[48]  M. Lemp,et al.  Corneal epithelial cell movement in humans , 1989, Eye.

[49]  F. Sundler,et al.  Occurrence and distribution of neuropeptides in the human skin. An immunocytochemical and immunochemical study on normal skin and blister fluid from inflamed skin. , 1987, Acta dermato-venereologica.

[50]  B. Holden,et al.  Evidence for sympathetic neural influence on human corneal epithelial function , 1985, Acta ophthalmologica.

[51]  J. Friend,et al.  The X, Y, Z hypothesis of corneal epithelial maintenance. , 1983, Investigative ophthalmology & visual science.

[52]  A. Cuello,et al.  Substance P-immunoreactive nerves in the human cornea and iris. , 1982, Investigative ophthalmology & visual science.

[53]  D. Maurice,et al.  The distribution and movement of serum albumin in the cornea. , 1965, Experimental eye research.

[54]  A. Laslop,et al.  Neurokinin a is a main constituent of sensory neurons innervating the anterior segment of the eye. , 2005, Investigative ophthalmology & visual science.

[55]  J. Lehtosalo.  Substance P-like immunoreactive trigeminal ganglion cells supplying the cornea , 2004, Histochemistry.

[56]  A. Kanai,et al.  [Endogenous substance P in corneal epithelial cells and keratocytes]. , 2001, Nippon Ganka Gakkai zasshi.

[57]  D. Tanelian,et al.  CGRP increases the rate of corneal re-epithelialization in an in vitro whole mount preparation. , 1996, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[58]  T. Amemiya,et al.  Immunohistochemical localization of basic fibroblast growth factor, platelet derived growth factor, transforming growth factor-beta and tumor necrosis factor-alpha in the pterygium. , 1996, Acta histochemica.

[59]  J. Auran,et al.  Scanning slit confocal microscopic observation of cell morphology and movement within the normal human anterior cornea. , 1995, Ophthalmology.

[60]  E. van der Zypen,et al.  [Ultrastructural studies on the pterygium. II. Connective tissue, vessels and nerves of the conjunctival part (author's transl)]. , 1975, Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. Albrecht von Graefe's archive for clinical and experimental ophthalmology.

[61]  Bron Aj.  Vortex patterns of the corneal epithelium. , 1973 .