Diabetes mellitus and septic shock increase the incidence of mortality by thrombosis. Although kinin B1 receptor (B1R) is involved in both pathologies, its role in platelet function and thrombosis remains unknown. This study investigates the expression, the inflammatory, and pro-thrombotic effects of B1R in a model of septic shock in diabetic rats. Sprague-Dawley rats were made diabetic with streptozotocin (STZ) (65 mg/kg, i.p.). Four days later, control and STZ-diabetic rats were injected with lipopolysaccharide (LPS) (2 mg/kg, i.p.) or the vehicle. B1R antagonist (SSR240612, 10 mg/kg by gavage) was given either acutely (12 and 24 h prior to endpoint analysis) or daily for up to 7 days. Moreover, a 7-day treatment was given either with cyclooxygenase (COX)-2 inhibitor (niflumic acid, 5 mg/kg, i.p.), non-selective COX-1 and COX-2 inhibitor (indomethacin, 10 mg/kg, i.p.), non-selective nitric oxide synthase (NOS) inhibitor (L-NAME, 50 mg/kg by gavage), iNOS inhibitor (1400W, 5 mg/kg, i.p.), or heparin (100 IU/kg, s.c.). The following endpoints were measured: edema and vascular permeability (Evans blue dye), B1R expression (qRT-PCR, western blot, flow cytometry), aggregation in platelet-rich plasma (optical aggregometry), and organ damage (histology). Rats treated with STZ, LPS, and STZ plus LPS showed significant increases in edema and vascular permeability (heart, kidney, lung, and liver) and increased expression of B1R in heart and kidney (mRNA) and platelets (protein). Lethal septic shock induced by LPS was enhanced in STZ-diabetic rats and was associated with lung and kidney damage, including platelet micro-aggregate formation. SSR240612 prevented all these abnormalities as well as STZ-induced hyperglycemia and LPS-induced hyperthermia. Similarly to SSR240612, blockade of iNOS and COX-2 improved survival. Data provide the first evidence that kinin B1R plays a primary role in lethal thrombosis in a rat model of septic shock in diabetes. Pharmacological rescue was made possible with B1R antagonism or by inhibition of iNOS and COX-2, which may act as downstream mechanisms.

Environmental factors are believed to play an important role in the pathogenesis of systemic sclerosis (SSc). Silica exposure has been implicated as potentially hazardous in epidemiological studies of SSc. It can activate fibroblasts to express profibrotic genes at certain conditions. The aim of this study is to examine whether the fibroblasts of SSc patients respond to silica particles with specific gene expressions differentially from normal control fibroblasts. The fibroblasts obtained from skin biopsies of 96 SSc patients and 104 controls were examined. Silica particles were used to perturb the cultures of the fibroblasts in time-course and dose-response assays. The transcript levels of COL1A2, COL3A1, MIVIP1, MMP3, TIMP3 and CTGF genes of the fibroblasts were measured with quantitative RT-PCR. The results showed that the expressions of all six genes in SSc fibroblasts under silica perturbation appeared significantly different from normal control fibroblasts. In age stratified analysis, compared to control fibroblasts, SSc fibroblasts from patients at age 30-40 years and 50-60 years displayed significantly decreased expressions of MMP1 gene in all dosage assays and increased expression of COL3A1 genes started at low dosages perturbation of silica particles, respectively. In autoantibody stratified analysis, specific gene expression patterns were significantly associated with autoantibody-subgroups of fibroblasts. A common feature of SSc fibroblasts was unstable and a wide range of gene expression changes in response to silica perturbation. Our studies may suggest an altered intrinsic dynamic control in SSc fibroblasts. In addition, sensitivity and specificity of SSc fibroblasts to potentially hazardous environmental trigger is age and autoantibody-subgroup-dependent. The fibroblasts of SSc patients at age 30-60 years may be more sensitive to silica perturbation toward a profibrotic gene expression.

Due to the severe adverse effects that can accompany conventional therapies for Crohn's disease, the search for natural complementary therapies has increased dramatically in recent years. Indole-3-carbinol (I3C), a constituent of cruciferous vegetables, possesses anti-inflammatory properties; however, its effects on intestinal inflammation have yet to be evaluated. To test the hypothesis that I3C dampens intestinal inflammation, C57Bl/6 mice were treated with I3C and exposed to 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis. Several parameters of disease severity and inflammation were subsequently evaluated. I3C dampened the disease severity, as indicated by decreased body weight loss and decreased severity of clinical signs. Interestingly, this effect was observed in female but not male mice, which displayed a trend towards exacerbated colitis. Differential effects were observed in the profiles of cytokine production, as the production of pro-inflammatory cytokines was increased in males. The sex-specific effect of I3C in TNBS-induced colitis is a novel finding and warrants further investigation since this is a common dietary compound and is also available commercially.