Novel approach to inhibit asthma-mediated lung inflammation using anti-CD147 intervention

Extracellular cyclophilins have been well described as chemotactic factors for various leukocyte subsets. This chemotactic capacity is dependent upon interaction of cyclophilins with the cell surface signaling receptor CD147. Elevated levels of extracellular cyclophilins have been documented in several inflammatory diseases. We propose that extracellular cyclophilins, via interaction with CD147, may contribute to the recruitment of leukocytes from the periphery into tissues during inflammatory responses. In this study, we examined whether extracellular cyclophilin-CD147 interactions might influence leukocyte recruitment in the inflammatory disease allergic asthma. Using a mouse model of asthmatic inflammation, we show that 1) extracellular cyclophilins are elevated in the airways of asthmatic mice; 2) mouse eosinophils and CD4+ T cells express CD147, which is up-regulated on CD4+ T cells upon activation; 3) cyclophilins induce CD147-dependent chemotaxis of activated CD4+ T cells in vitro; 4) in vivo treatment with anti-CD147 mAb significantly reduces (by up to 50%) the accumulation of eosinophils and effector/memory CD4+ T lymphocytes, as well as Ag-specific Th2 cytokine secretion, in lung tissues; and 5) anti-CD147 treatment significantly reduces airway epithelial mucin production and bronchial hyperreactivity to methacholine challenge. These findings provide a novel mechanism whereby asthmatic lung inflammation may be reduced by targeting cyclophilin-CD147 interactions.     

Immune responses to stress after stress management training in patients with rheumatoid arthritis

Introduction

Psychological stress may alter immune function by activating physiological stress pathways. Building on our previous study, in which we report that stress management training led to an altered self-reported and cortisol response to psychological stress in patients with rheumatoid arthritis (RA), we explored the effects of this stress management intervention on the immune response to a psychological stress task in patients with RA.

Methods

In this study, 74 patients with RA, who were randomly assigned to either a control group or a group that received short stress management training, performed the Trier Social Stress Test (TSST) 1 week after the intervention and at a 9-week follow-up. Stress-induced changes in levels of key cytokines involved in stress and inflammatory processes (for example, interleukin (IL)-6 and IL-8) were assessed.

Results

Basal and stress-induced cytokine levels were not significantly different in patients in the intervention and control groups one week after treatment, but stress-induced IL-8 levels were lower in patients in the intervention group than in the control group at the follow-up assessment.

Conclusions

In line with our previous findings of lower stress-induced cortisol levels at the follow-up of stress management intervention, this is the first study to show that relatively short stress management training might also alter stress-induced IL-8 levels in patients with RA. These results might help to determine the role of immunological mediators in stress and disease.

Trial registration

The Netherlands National Trial Register (NTR1193)     

Synthetic liposomes are protective from bleomycin-induced lung toxicity

Idiopathic pulmonary fibrosis is a devastating disease characterized by a progressive, irreversible, and ultimately lethal form of lung fibrosis. Except for lung transplantation, no effective treatment options currently exist. The bleomycin animal model is one of the best studied models of lung injury and fibrosis. A previous study using mouse tumor models observed that liposome-encapsulated bleomycin exhibited reduced lung toxicity. Therefore, we hypothesized that airway delivery of synthetic phosphatidylcholine-containing liposomes alone would protect mice from bleomycin-induced lung toxicity. C57BL/6 mice were administered uncharged multilamellar liposomes (100 μl) or PBS vehicle on day 0 by airway delivery. Bleomycin (3.33 U/kg) or saline vehicle was then given intratracheally on day 1 followed by four additional separate doses of liposomes on days 4, 8, 12, and 16. Fluorescent images of liposomes labeled with 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate confirmed effective and widespread delivery of liposomes to the lower respiratory tract as well as uptake primarily by alveolar macrophages and to a lesser extent by type II alveolar epithelial cells. Results at day 22, 3 wk after bleomycin treatment, showed that airway delivery of liposomes before and after intratracheal administration of bleomycin significantly reduced bleomycin-induced lung toxicity as evidenced by less body weight loss, chronic lung inflammation, and fibrosis as well as improved lung compliance compared with controls. These data indicate that airway-delivered synthetic liposomes represent a novel treatment strategy to reduce the lung toxicity associated with bleomycin in a mouse model.