THE CXC CHEMOKINES, IL-8 AND IP-10, REGULATE ANGIOGENIC ACTIVITY IN IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal disor der, Fibroplasia and deposition of extracellular matrix are dependent, in part, on angiogenesis, We postulated that an imbalance exists in t he expression of angiogenic (IL-8) vs angiostatic (IFN-gamma-inducible protein (IP-10)) CXC chemokines, which favors net angiogenesis in IPF , To test this hypothesis, we obtained open lung biopsies either from normal patients undergoing thoracic surgery for reasons other than int erstitial lung disease (control) or from patients with IPF. We found t hat levels of IL-8 were greater from tissue specimens of IPF patients then from those of controls, In contrast, IP-10 levels were higher fro m tissue specimens obtained from control subjects than from those from IPF patients, When IL-8 or IP-10 was depleted from IPF tissue specime ns, tissue-derived angiogenic activity was markedly reduced or enhance d, respectively. Immunolocalization of IL-8 demonstrated th!at the pul monary fibroblast (PF) of IPF lung was the predominant cellular source of IL-8, Isolated PF from IPF patients constitutively produced more I L-8 and less IP-10 than control PF, Conditioned media from IPF-PFs dem onstrated constitutive angiogenic activity that was attributable, in p art, to IL-8, Depletion of IP-10 from IPF-PF CM resulted in an increas e in corneal neovascularization. These findings support the notion tha t IL-8 and IP-10 are important factors that regulate angiogenic activi ty in IPF.