The role of CXC chemokines in pulmonary fibrosis

The CXC chemokine family is a pleiotropic family of cytokines that are involved in promoting the trafficking of various leukocytes, in regulating angiogenesis and vascular remodeling, and in promoting the mobilization and trafficking of mesenchymal progenitor cells such as fibrocytes. These functions of CXC chemokines are important in the pathogenesis of pulmonary fibrosis and other fibroproliferative disorders. In this Review, we discuss the biology of CXC chemokine family members, specifically as it relates to their role in regulating vascular remodeling and trafficking of circulating mesenchymal progenitor cells (also known as fibrocytes) in pulmonary fibrosis.     

Novel stem/progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential

The airway epithelium is in direct contact with the environment and therefore constantly at risk for injury. Basal cells (BCs) have been found to repair the surface epithelium (SE), but the contribution of other stem cell populations to airway epithelial repair has not been identified. We demonstrated that airway submucosal gland (SMG) duct cells, in addition to BCs, survived severe hypoxic-ischemic injury. We developed a method to isolate duct cells from the airway. In vitro and in vivo models were used to compare the self-renewal and differentiation potential of duct cells and BCs. We found that only duct cells were capable of regenerating SMG tubules and ducts, as well as the SE overlying the SMGs. SMG duct cells are therefore a multipotent stem cell for airway epithelial repair This is of importance to the field of lung regeneration as determining the repairing cell populations could lead to the identification of novel therapeutic targets and cell-based therapies for patients with airway diseases.     

IL-13 regulates cilia loss and foxj1 expression in human airway epithelium

Mucociliary clearance is essential to the defense mechanisms of the respiratory system. Loss of normal mucociliary clearance contributes to the pathogenesis of genetic and acquired lung diseases. Treatment of cultured differentiated human airway epithelial tissue with IL-13 resulted in a loss of ciliated epithelial cells and an increase in mucus-secreting cells. The loss of ciliated cells was characterized by mislocation of basal bodies and loss of ezrin from the apical cell compartment. In addition to the loss of ciliated cells and increase in mucous cells after IL-13 treatment, cells with characteristics of both ciliated and mucous cells were observed in the airway epithelium. In association with the decrease in ciliated cells after IL-13 treatment, there was noted a decrease in foxj1 expression in the airway epithelium, characterized by a decrease in the number of foxj1-expressing cells. Within the foxj1 promoter, a STAT-binding element was identified and inhibition of foxj1 expression by STAT-6 and IL-13 was demonstrated. These findings suggest molecular and cellular mechanisms for cilia loss in pulmonary disease. Inhibition of foxj1 expression results in loss of apical localization of ezrin and basal bodies with subsequent loss of axonemal structures. These findings have important implications for the pathogenesis and treatment of airway diseases.     

Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft- versus-host disease

Forty-eight patients with chronic myelocytic leukemia, aged 11 to 47, were treated with high-dose cyclophosphamide and fractionated total body irradiation, followed by infusion of marrow from HLA-identical siblings. They were randomized to receive either methotrexate (MTX) (n = 23) or cyclosporine (CSP) (n = 25) as postgrafting prophylaxis for graft-v-host disease (GVHD). All patients had evidence of sustained hematopoietic engraftment. Seventeen of the 25 patients receiving CSP and 17 of the 23 patients receiving MTX are alive between one and almost four (median, 1.7) years, with an actuarial survival rate at three years of 62% and 66%, respectively (P = .60). Also, with respect to most other parameters studied, the two drugs were identical. The probability of acute GVHD was .42 and .46, respectively (P = .70), that of chronic GVHD, .50 and .63 (P = .44), and that of death from transplant-related causes, .30 and .24 (P = .51). There were no differences in the speed of granulocyte and platelet engraftment (P = .82 and .94, respectively), and the duration of hospitalization was comparable (P = .58). Patients receiving MTX required red cell transfusions for a shorter period of time (P = .02), but had a slightly increased morbidity from early oral mucositis. The leukemia recurrence rates were comparable (P = .60). With the regimens used in this study, we conclude that CSP failed to reduce the incidence of GVHD and improve the survival of patients with chronic myelocytic leukemia when compared to results with standard MTX.