Duration of Reduction in Enduring Stress-Induced Hyperalgesia Via FKBP51 Inhibition Depends on Timing of Administration Relative to Traumatic Stress Exposure.

Chronic pain development is a frequent outcome of severe stressor exposure, with or without tissue injury. Enduring stress-induced hyperalgesia (ESIH) is believed to play a central role, but the precise mechanisms mediating the development of chronic post-traumatic pain, and the time-dependency of these mechanisms, remain poorly understood. Clinical and preclinical data suggest that the inhibition of FK506-binding protein 51 (FKBP51), a key stress system regulator, might prevent ESIH. We evaluated whether peritraumatic inhibition of FKBP51 in an animal model of traumatic stress exposure, the single prolonged stress (SPS) model, reversed ESIH evaluated via daily mechanical von Frey testing. FKBP51 inhibition was achieved using SAFit2, a potent and specific small molecule inhibitor of FKBP51, administered to male and female Sprague-Dawley rats via intraperitoneal injection. To assess timing effects, FKBP51 was administered at different times relative to stress (SPS) exposure. SAFit2 administration immediately after SPS produced a complete reversal in ESIH lasting >7 days. In contrast, SAFit2 administration 72 hours following SPS produced only temporary hyperalgesia reversal, and administration 120h following SPS had no effect. Similarly, animals undergoing SPS together with tissue injury (plantar incision) receiving SAFit2 immediately post-surgery developed acute hyperalgesia but recovered by 4 days and did not develop ESIH. These data suggest that: 1) FKBP51 plays an important, time-dependent role in ESIH pathogenesis, 2) time windows of opportunity may exist to prevent ESIH via FKBP51 inhibition after traumatic stress, with or without tissue injury, and 3) the use of inhibitors of specific pathways may provide new insights into chronic post-traumatic pain development. PERSPECTIVE: The current work adds to a growing body of literature indicating that FKBP51 inhibition is a highly promising potential treatment strategy for reducing hyperalgesia. In the case of post-traumatic chronic pain, we show that such a treatment strategy would be particularly impactful if administered early after traumatic stress exposure.

Anticoagulation increases alveolar hemorrhage in mice infected with influenza A.

Influenza A virus infection is a common respiratory tract infection. Alveolar hemorrhage has been reported in patients with influenza pneumonia and in mice infected with influenza A. In this study, we investigated the effect of two anticoagulants on alveolar hemorrhage after influenza A virus (IAV) infection of wild-type mice. Wild-type mice were anticoagulated with either warfarin or the direct thrombin inhibitor dabigatran etexilate and then infected with a mouse-adapted influenza virus (A/Puerto Rico/8/34 H1N1). Alveolar hemorrhage was assessed by measuring hemoglobin levels in the bronchoalveolar lavage fluid (BALF). We also measured vascular permeability and viral genomes in the lung, as well as white blood cells, inflammatory mediators, and protein in BALF Survival and body weight were monitored for 14 days after influenza A infection. In infected mice receiving either warfarin or dabigatran etexilate we observed decreased activation of coagulation in the BALF and increased alveolar hemorrhage. Warfarin but not dabigatran etexilate increased vascular permeability and mortality of influenza A-infected mice. Anticoagulation did not affect levels of influenza A genomes, white blood cells, inflammatory mediators, or protein in the BALF Our study indicates that systemic anticoagulation increases alveolar hemorrhage in influenza A-infected mice.

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease.

Activation of coagulation and vascular inflammation are prominent features of sickle cell disease (SCD). Previously, we have shown that inhibition of tissue factor (TF) attenuates activation of coagulation and vascular inflammation in mouse models of SCD. In this study, we examined the mechanism by which coagulation proteases enhance vascular inflammation in sickle BERK mice. To specifically investigate the contribution of FXa and thrombin, mice were fed chow containing either rivaroxaban or dabigatran, respectively. In addition, we used bone marrow transplantation to generate sickle mice deficient in either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) on nonhematopoietic cells. FXa inhibition and PAR-2 deficiency in nonhematopoietic cells attenuated systemic inflammation, measured by plasma levels of interleukin-6 (IL-6). In contrast, neither thrombin inhibition nor PAR-1 deficiency in nonhematopoietic cells affected plasma levels of IL-6 in sickle mice. However, thrombin did contribute to neutrophil infiltration in the lung, independently of PAR-1 expressed by nonhematopoietic cells. Furthermore, the TF-dependent increase in plasma levels of soluble vascular cell adhesion molecule-1 in sickle mice was not mediated by FXa or thrombin. Our data indicate that TF, FXa, and thrombin differentially contribute to vascular inflammation in a mouse model of SCD.