The Expression Of CXCR4 And Its Role In Pulmonary Fibrosis Model In Rats

Pulmonary fibrosis is a chronic and often fatal pulmonarydisorder with a survival rate as low as 30% 5 years after diagnosis.The pathogenesis of pulmonary fibrosis is characterized bydysregulated and inappropriate tissue remodeling and enhancedvascular remodeling, fibroproliferation, and deposition of ECM.Without resolution, continued fibrosis leads to loss of lung functionand ultimately death. Tissue fibroblasts have classically been heldto be responsible for repair and remodeling within the lung,although this view has been challenged since those fibroblastsobserved in the fibrotic lung show phenotypic differences to theircounterparts in the lungs of healthy individuals. Thus, it is possiblethat, in common with their perceived role in fibrosis and woundrepair, circulating fibrocytes may also be recruited to injured lungsas an integral component of the pathogenesis of pulmonary fibrosis.And fibrocytes migrates and traffics to the lungs in response toCXCL12 and CXCR4.Chemokines comprise four supergene families, two of thesefamilies (the CC and CXC chemokine groups) are quite large andcontain over 50 identified ligands and at least 14 individualreceptors. In addition to their originally identified chemotacticactivity, chemokines possess a variety of biological activities,ranging from immunomodulating leukocyte activation tosuppressing HIV infection. A number of in vitro and in vivo studieshave underscored the importance of chemokine biology in theprogression of both acute and chronic lung diseases. Theseinvestigations have demonstrated the importance of targetingchemokines for new therapeutic approaches to treat pulmonarydisease. A variety of acute and chronic lung diseases have beenshown to possess a chemokine component and contribute to theinitiation and maintenance of lung pathology, thus, there is littledoubt that a further understanding of the mechanisms of pulmonarydiseases will rely upon advances in the field of chemokine biology.In this study,we established a bleomycin-induced pulmonaryfibrosis model in rats and examined the expression of CXCR4 tofind out the possible effect of CXCR4 in pulmonary fibrosis.The pulmonary fibrosis model was successfullyestablished .The results of RT-PCR demonstrate the expression ofCXCR4 increased in lungs of pulmonary fibrosis model than inlungs of saline control group.The possible mechanism of CXCR4in pulmonary fibrosis is as follows:There is recent evidence of circulating blood cells (termed"fibrocytes") that possess fibroblast-like properties and that can bechemotactically recruited to sites of tissue injury. Combined withthe recent evidence of BM stem cell plasticity cited above. Aninflux of BM-derived cells into the lung in fibrosis requires thatsome induced signal in the lung is capable of recruiting theseextrapulmonary cells. More recently and directly relevant to theBM-derived precursor cells, peripheral blood–derived fibrocytesare shown to express chemokine receptors such as CCR7 andCXCR4, and could migrate toward SDF-1α (CXCR4 ligand).Theprobable cellular sources for these chemokines are likely to beresident lung fibroblasts, or endothelial and/or epithelial cells.Some in vivo studies support the notion that the systemicaddition of specific neutralizing anti-CXCL12 Ab's reduceintrapulmonary recruitment of CD45+Col I+CXCR4+ fibrocytes andsignificantly attenuate lung fibrosis.Lung fibrosis is not completelyabolished by treatment with anti-CXCL12 Ab's, however. Thus, itis possible that other mechanisms could be involved in theintrapulmonary recruitment of fibrocytes and the associateddevelopment of lung fibrosis. In this respect, CCR7 is anotherchemokine receptor that has been shown to be important in theregulated movement of fibrocytes.In this study,we observed that the expression of CXCR4 inlungs of days 7 and 14 are higher than in lungs of days 28(P<0.01,respectively).The results suggest that circulating fibrocytes mayultimately differentiate into myofibroblasts within the lungs stems.Another factor that may determine the fate of fibrocytesduring pulmonary fibrosis is apoptosis. CXCR4+ fibrocytes may beideally situated to avoid programmed cell death since ligation ofCXCR4 by CXCL12 has been shown to regulate the cell deathmachinery through downstream activation of the PI3K, AKT, andMAP kinase pathways.In conclusion, we have shown, we suggest that CXCR4 maycontribute to the pathogenesis of pulmonary fibrosis. The cellsexpressed CXCR4 offer a novel therapeutic target for developingmore effective treatments against this devastating disease.