The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling.

We found upregulation of expression of the microRNA miR-155 in primary effector and effector memory CD8(+) T cells, but low miR-155 expression in naive and central memory cells. Antiviral CD8(+) T cell responses and viral clearance were impaired in miR-155-deficient mice, and this defect was intrinsic to CD8(+) T cells, as miR-155-deficient CD8(+) T cells mounted greatly diminished primary and memory responses. Conversely, miR-155 overexpression augmented antiviral CD8(+) T cell responses in vivo. Gene-expression profiling showed that miR-155-deficient CD8(+) T cells had enhanced type I interferon signaling and were more susceptible to interferon's antiproliferative effect. Inhibition of the type I interferon-associated transcription factors STAT1 or IRF7 resulted in enhanced responses of miR-155-deficient CD8(+) T cells in vivo. We have thus identified a previously unknown role for miR-155 in regulating responsiveness to interferon and CD8(+) T cell responses to pathogens in vivo.

Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion.

The failure of CD8(+) T cells to respond to chronic infection has been termed "exhaustion" and describes the condition in which CD8(+) T cells exhibit reduced differentiation, proliferation, and effector function. CD8(+) T cell exhaustion has been extensively studied in the murine model of chronic infection, lymphocytic choriomeningitis virus (LCMV). Although LCMV-based studies have yielded many interesting findings, they have not allowed for discrimination between the roles of cytokine- and Ag-driven exhaustion. We have created a system of chronic Ag stimulation using murine influenza A virus that leads to exhaustion and functional disability of virus-specific CD8(+) T cells, in the absence of high viral titers, sustained proinflammatory cytokine production and lymphocyte infection. Our findings show that Ag alone is sufficient to drive CD8(+) T cell impairment, that Ag-driven loss of virus-specific CD8(+) T cells is TRAIL mediated, and that removal of Ag reverses exhaustion. Although programmed death 1 was up-regulated on chronic Ag-stimulated CD8(+) T cells, it played no role in the exhaustion. These findings provide a novel insight into the mechanisms that control functional exhaustion of CD8(+) T cells in chronic infection.

Using pressure-volume curves to set proper PEEP in acute lung injury.

The evolution of respiratory care on patients with acute respiratory distress syndrome (ARDS) has been focused on preventing the deleterious effects of mechanical ventilation, termed ventilator-induced lung injury (VILI). Currently, reduced tidal volume is the standard of ventilatory care for patients with ARDS. The current focus, however, has shifted to the proper setting of positive end-expiratory pressure (PEEP). The whole lung pressure-volume (P/V) curve has been used to individualize setting proper PEEP in patients with ARDS, although the physiologic interpretation of the curve remains under debate. The purpose of this review is to present the pros and cons of using P/V curves to set PEEP in patients with ARDS. A systematic analysis of recent and relevant literature was conducted. It has been hypothesized that proper PEEP can be determined by identifying P/V curve inflection points. Acquiring a dynamic curve presents the key to the curve's bedside application. The lower inflection point of the inflation limb has been shown to be the point of massive alveolar recruitment and therefore an option for setting PEEP. However, it is becoming widely accepted that the upper inflection point (UIP) of the deflation limb of the P/V curve represents the point of optimal PEEP. New methods used to identify optimal PEEP, including tomography and active compliance measurements, are currently being investigated. In conclusion, we believe that the most promising method for determining proper PEEP settings is use of the UIP of the deflation limb. However, tomography and dynamic compliance may offer superior bedside availability.

Absence of alveolar tears in rat lungs with significant alveolar instability.

BACKGROUND: Lung injury associated with the acute respiratory distress syndrome can be exacerbated by improper mechanical ventilation creating a secondary injury known as ventilator-induced lung injury (VILI). We hypothesized that VILI could be caused in part by alveolar recruitment/derecruitment resulting in gross tearing of the alveolus. OBJECTIVES: The exact mechanism of VILI has yet to be elucidated though multiple hypotheses have been proposed. In this study we tested the hypothesis that gross alveolar tearing plays a key role in the pathogenesis of VILI. METHODS: Anesthetized rats were ventilated and instrumented for hemodynamic and blood gas measurements. Following baseline readings, rats were exposed to 90 min of either normal ventilation (control group: respiratory rate 35 min(-1), positive end-expiratory pressure 3 cm H(2)O, peak inflation pressure 14 cm H(2)O) or injurious ventilation (VILI group: respiratory rate 20 min(-1), positive end-expiratory pressure 0 cm H(2)O, peak inflation pressure 45 cm H(2)O). Parameters studied included hemodynamics, pulmonary variables, in vivo video microscopy of alveolar mechanics (i.e. dynamic alveolar recruitment/derecruitment) and scanning electron microscopy to detect gross tears on the alveolar surface. RESULTS: Injurious ventilation significantly increased alveolar instability after 45 min and alveoli remained unstable until the end of the study (electron microscopy after 90 min revealed that injurious ventilation did not cause gross tears in the alveolar surface). CONCLUSIONS: We demonstrated that alveolar instability induced by injurous ventilation does not cause gross alveolar tears, suggesting that the tissue injury in this animal VILI model is due to a mechanism other than gross rupture of the alveolus.