Characterization of the mechanism of action of lanraplenib, a novel spleen tyrosine kinase inhibitor, in models of lupus nephritis.

BACKGROUND: B cells are critical mediators of systemic lupus erythematosus (SLE) and lupus nephritis (LN), and antinuclear antibodies can be found in the serum of approximately 98% of patients with SLE. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that mediates signaling from immunoreceptors, including the B cell receptor. Active, phosphorylated SYK has been observed in tissues from patients with SLE or cutaneous lupus erythematosus, and its inhibition is hypothesized to ameliorate disease pathogenesis. We sought to evaluate the efficacy and characterize the mechanism of action of lanraplenib, a selective oral SYK inhibitor, in the New Zealand black/white (NZB/W) murine model of SLE and LN. METHODS: Lanraplenib was evaluated for inhibition of primary human B cell functions in vitro. Furthermore, the effect of SYK inhibition on ameliorating LN-like disease in vivo was determined by treating NZB/W mice with lanraplenib, cyclophosphamide, or a vehicle control. Glomerulopathy and immunoglobulin G (IgG) deposition were quantified in kidneys. The concentration of proinflammatory cytokines was measured in serum. Splenocytes were analyzed by flow cytometry for B cell maturation and T cell memory maturation, and the presence of T follicular helper and dendritic cells. RESULTS: In human B cells in vitro, lanraplenib inhibited B cell activating factor-mediated survival as well as activation, maturation, and immunoglobulin M production. Treatment of NZB/W mice with lanraplenib improved overall survival, prevented the development of proteinuria, and reduced blood urea nitrogen concentrations. Kidney morphology was significantly preserved by treatment with lanraplenib as measured by glomerular diameter, protein cast severity, interstitial inflammation, vasculitis, and frequency of glomerular crescents; treatment with lanraplenib reduced glomerular IgG deposition. Mice treated with lanraplenib had reduced concentrations of serum proinflammatory cytokines. Lanraplenib blocked disease-driven B cell maturation and T cell memory maturation in the spleen. CONCLUSIONS: Lanraplenib blocked the progression of LN-like disease in NZB/W mice. Human in vitro and murine in vivo data suggest that lanraplenib may be efficacious in preventing disease progression in patients with LN at least in part by inhibiting B cell maturation. These data provide additional rationale for the use of lanraplenib in the treatment of SLE and LN.

Achievement of effective cardiopulmonary trauma surgical skills training throughout the incorporation of a low-cost and easy to implement pulsatile simulation model.

OBJECTIVES: . In the last decade, concern regarding the preparedness of general surgery graduates to effectively manage thoracic trauma cases has been raised. However, due to limited availability and elevated costs, access to cardiopulmonary trauma simulation models is limited. This article describes our experience implementing a low-cost blended ex vivo tissue-based simulation model using animal by-products that incorporates pump perfusion and ventilation. DESIGN: . Firstly, for validation purposes 8 junior residents, 8 recently graduated general surgeons, and 3 cardiothoracic surgery attendings from Pontificia Universidad Católica de Chile Clinical Hospital were recruited. Proficiency in performing a pulmonary tractotomy and a myocardial injury repair was assessed with global and specific rating scales. Secondly, to evaluate the effectiveness of the model as a learning tool, 16 general surgery residents from different programs across the country were recruited receiving intensive, personalized training on the models. Proficiency was measured before and after the training. RESULTS: . For the validation phase, significant differences among groups according to the previous level of expertise were shown, and therefore construct validity was established. The results of the second phase showed a significant overall improvement in participant's performance. CONCLUSION: . Effective training and assessment for advanced surgical skills in cardiothoracic trauma can be achieved using a low-cost pulsatile simulation model.