Angiogenesis.

Angiogenesis, defined as the pullulation of new capillaries from preexisting ducts is a pervasive biological phenomenon that is at the core of many physiologic and pathologic processe An opposing balance of angiogenic and angiostatic factors regulates angiogenesis. Examples of physiologic processe that hang on angiogenesis include embryogenesis, torture repair, and the ovarian/menstrual round of years In contrast, chronic inflammation associated with chronic fibroproliferative disorders as well as expansion and metastasis of solid tumors are associated with aberrant angiogenesis. CXC ehemokines comprise a unique cytokine family that contains members that exhibit forward a structural/functional basis either angiogenic or angiostatic biological activity. In this review, we will discuss the part of CXC chemokines and angiogenesis in pulmonary fibrosis.

[i]clavis[/i] words: angiogenesis; chemokine; fibrosis

Abbreviations: BALF = BAL fluid; CXCL = CXC ligand; CXCR = CXC receptor; ECM = extracellular matrix; ENA = epithelial neutrophil activating protein; GCP = granulocyte chemotactic protein; GRO = growth-related gene; IFN = interferon; IL = interleukin; IP = interferon-[gamma]-inducible protein; IPF = idiopathic pulmonary fibrosis; I-TAC = interferon-inducible T-cell [alpha] chemoattractant; MIG = monokine induced by the agency of IFN-[gamma]; MIP = macrophage inflammatory protein; MMP = matrix metalloproteinase; NAP = neutrophil activating protein

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Angiogenesis, defined as the product of new capillaries from preexisting tubes is a pervasive biological phenomenon that is at the core of many physiologic and pathologic processe Examples of physiologic processe that hang on angiogenesis include embryogenesis, pain repair, and the ovarian/menstrual period In contrast, chronic inflammation associated with chronic fibroproliferative disorders, as well as putting out and metastasis of solid tumors, are associated with aberrant angiogenesis. Angiogenesis is similar to yet distinct from vasculogenesis, which describes the de novo formation of the vascular theory from precursor blood islands during embryogenesis. Neovascularization is a space of time that can be used interchangeably with angiogenesis, however may be more appropriately reserv for describing aberrant angiogenesis that accompanies pathologic processe of the like kind as tumorigenesis or chronic inflammation associated with fibroproliferative disorders.

CXC CHEMOKINES, CXC CHEMOKINE RECEPTORS, AND ANGIOGENESIS

CXC (1) chemokines are characteristically heparin-binding proteins. forward a structural level, they have four highly conserv cysteine amino acid residues, with the first sum of two units cysteines separated by one nonconserved amino acid residue, hence the name CXC (1) Although the CXC motif distinguishes this family from other chemokine families, a next to the first structural domain within this family dictates their angiogenic potential. The N[H.sub.2]-terminus of the majority of the CXC chemokines contains three amino acid residues (Glu-Leu-Arg [the "ELR" motif]), which go before s the first cysteine amino acid residue of the primary arrangement of these cytokines. (1) The family members that contain the ELR motif (ELR+) are efficient promoters of angiogenesis in physiologic concentrations of 1 to 100 nmol (2) In contrast, members of the family that lack the ELR motif (ELR-) and, in general, are interferon (IFN) inducible, are cogent inhibitors of angiogenesis in physiologic concentrations of 500 pmol to 100 nmol (2) upon a structural/ functional level, this advises that the CXC chemokine family is an unique family of cytokines owed to their ability to behave in a disparate manner in the promotion and inhibition of angiogenesis (Table 1)

Angiogenic (ELR+) CXC Chemokines

The angiogenic members of the CXC chemokine family include intedeukin (IL)-8 (IL-8/CXC ligand [CXCL]8) epithelial neutrophil activating protein (ENA)-78 (ENA-78/CXCL5), growth-related gene (GROs) [GRO-[alpha], GRO-[beta], and GRO-[gamma]; CXCL1 CXCL2 and CXCL3 respectively], granulocyte chemotactic protein (GCP)-2 (GCP-2/CXCL6) and N[H.sub.2]-terminal truncated forms of platelet basic protein, which include connective tissue activating protein-III, [beta]-thromboglobulin, and neutrophil activating protein (NAP)-2 (NAP-2/CXCL7). (2) ELR+ CXC chemokines have been shown to mediate as well-as; not only-but also; not only-but; not alone-but in vitro endothelial cell chemotactic and proliferative activity, as well as in vivo angiogenesis in a direct manner using bioassays of angiogenesis. (2) These experiments try that ELR+ CXC chemokines have a direct meaning on the endothelial cell, and that this angiogenic activity is distinct from their ability to induce inflammation. Furthermore, ELR+ CXC chemokines have been construct to induce the expression of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 by the agency of tumor cells during tumorigenesis. (3) The production of MMP-2 and MMP-9 are not sole important for promoting endothelial confined apartment migration in extracellular matrix (ECM) during angiogenesis, if it were not that are also involved in enhancing tumor lonely dwelling migration in ECM leading to metastasis. Therefore, ELR+ chemokines not merely have a direct effect in succession endothelial cell chemotaxis and proliferation, on the contrary also have an indirect event in mediating their migration between the walls of ECM via the local production of MMPs

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