Modulation of pulmonary fibrosis by IL-13Rα2.

Pulmonary fibrosis is a progressive and fatal disease that involves the remodeling of the distal airspace and the lung parenchyma, which results in compromised gas exchange. The median survival time once diagnosed is less than three years. Interleukin (IL)-13 has been shown to play a role in a number of inflammatory and fibrotic diseases. IL-13 modulates its effector functions via a complex receptor system that includes the IL-4 receptor (R) α, IL-13Rα1, and the IL-13Rα2. IL-13Rα1 binds IL-13 with low affinity, yet, when it forms a complex with IL-4α, it binds with much higher affinity, inducing the effector functions of IL-13. IL-13Rα2 binds IL-13 with high affinity but has a short cytoplasmic tail and has been shown to act as a nonsignaling decoy receptor. Transfection of fibroblasts and epithelial cells with IL-13Rα2 inhibited the IL-13 induction of soluble collagen, TGF-ß, and CCL17. Adenoviral overexpression of IL-13Rα2 in the lung reduced bleomycin-induced fibrosis. Our work shows that overexpression of IL-13Rα2 inhibits the IL-13 induction of fibrotic markers in vitro and inhibits bleomycin-induced pulmonary fibrosis. In summary our study highlights the antifibrotic nature of IL-13Ra2.

Airway responsiveness after acute exposure to urban particulate matter 1648 in a DO11.10 murine model.

Enhanced airway responsiveness (AR) is a well-established characteristic of asthma that epidemiological evidence has linked with inhalation of ambient particulate matter (PM). To determine whether acute exposure to urban particulate matter PM1648 can exacerbate airway responsiveness and alter the early inflammatory state, a unique murine model was created using DO11.10 mice, transgenic for a T cell receptor recognizing ovalbumin(323-339). Because these mice are sensitive to ovalbumin, immunization procedures involving adjuvant or long aerosolization procedures are not necessary and, therefore, allow for the study of an acute AR response to particulate and antigen in young animals. AR was assessed by barometric whole body plethysmography and measured by enhanced pause (Penh). PM1648 and ovalbumin were administered intranasally 72 and 4 h before to AR assessment, respectively. A dose-response relationship between PM1648 and Penh was determined, and doses at or above 500 microg had Penh values significantly higher than saline controls. Penh values of control particle titanium dioxide (TiO(2)) were similar to saline controls demonstrating no nonspecific particulate effect on AR. Lung lavage at time of AR assessment showed no significant inflammation due to particulate exposure or ovalbumin alone; however, PM1648/ovalbumin and TiO(2)/ovalbumin combinations resulted in significant neutrophilia. In addition, treatment with polymyxin B to remove surface-bound endotoxin did not significantly affect Penh levels. These results indicate that PM1648 specifically increases AR in a dose-dependent manner and that this exacerbation is not a direct response to increased neutrophil concentration, particle-bound endotoxin or nonspecific particle effects.

Environmental oxygen tension affects phenotype in cultured bone marrow-derived macrophages.

This study tested the hypothesis that the unique phenotype of alveolar macrophages (AM) is maintained through adaptation to the relatively high oxygen partial pressure (P(O2)) of the lung, through modification of redox-sensitive transcription factors. BALB/c mouse bone marrow-derived macrophages (BMC) were differentiated under different P(O2) and compared functionally to AM and peritoneal macrophages (PM). BMC differentiated in normoxia (P(O2) 140 Torr, BMC(high)) were similar to AM in having low phagocytic and antigen presenting cell (APC) activities. However, BMC grown in low oxygen tension as found in other tissues (<40 Torr, BMC(low)) were better phagocytes and APCs, similar to PM. BMC(high) were more oxidative intracellularly than BMC(low), based on oxidation of dichlorofluorescein and higher glutathione disulfide/glutathione (GSH) ratios, despite having more GSH. Finally, lipopolysaccharide-induced nuclear factor-kappaB translocation, measured by laser scanning cytometry, was reduced in BMC(high) and AM, compared with BMC(low) and PM, respectively. These data suggest that regulation of the AM phenotype may occur, at least in part, via inhibition of NF-kappaB by the unique redox environment.