Hypoxia Promotes the Expression of ADAM9 by Tubular Epithelial Cells which Enhances TGF-ß1 Activation and Promotes Tissue Fibrosis in Lupus Nephritis.

OBJECTIVE: Enhanced expression of transforming growth factor-beta (TGF-ß) in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end-organ damage. Disintegrin and metalloproteinases 9 (ADAM9) activate TGF-ß1 by cleaving the latency-associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGF-ß1. METHODS: We assessed the expression of ADAM9 in the kidneys of lupus-prone mice and humans. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the upregulation of ADAM9 and the subsequent activation of TGF-ß1. To assess the role of ADAM9 in the development of tubular-intestinal fibrosis in LN, we generated MRL/lpr. Adam9-deficient mice. RESULTS: ADAM9 was highly expressed in tubules from MRL/lpr. mice. The transcription factor hypoxia-inducible factor-1 alpha was found to promote the transcription of ADAM9 in TECs. TECs from Adam9-deficient mice exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGF-ß1 from latent TGF-ß1. Co-culture of TECs from Adam9-deficient mice with fibroblasts in the presence of dimethyloxalylglycine and latent TGF-ß1 produced decreased amounts of type I collagen and alpha-smooth muscle actin (α-SMA) by fibroblasts. Adam9-deficient MRL/lpr mice showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found increased. CONCLUSION: Hypoxia promotes the expression of ADAM9 by TECs which is responsible for the development of interstitial fibrosis in LN by enhancing the TGF-ß1 activation which promotes fibroblasts to produce collagen and α-SMA.

Infections in Patients with Systemic Lupus Erythematosus: The Contribution of Primary Immune Defects Versus Treatment-Induced Immunosuppression.

Patients with systemic lupus erythematosus experience high rates of infections. The use of immunosuppressive drugs to treat the disease, along with the fact that both the innate and adaptive branches of the immune system are compromised, account for the development of infections. In this communication, we briefly discuss the aberrant function of the immune system in patients with systemic lupus erythematosus and review the occurrence of infections that have been reported in clinical trials conducted to develop new therapeutics. Understanding the immune dysfunction in patients with systemic lupus erythematosus and the appearance of infections while trying to control the disease using immunosuppressive or immunomodulatory drugs should help limit infections and mitigate the associated morbidity and mortality.

Non-thyroidal illness syndrome predicts outcome in adult critically ill patients: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis to comprehensively determine the prevalence and the prognostic role of non-thyroidal illness syndrome (NTIS) in critically ill patients. We included studies that assessed thyroid function by measuring the serum thyroid hormone (TH) level and in-hospital mortality in adult septic patients. Reviews, case reports, editorials, letters, animal studies, duplicate studies, and studies with irrelevant populations and inappropriate controls were excluded. A total of 6869 patients from 25 studies were included. The median prevalence rate of NTIS was 58% (IQR 33.2-63.7). In univariate analysis, triiodothyronine (T3) and free T3 (FT3) levels in non-survivors were relatively lower than that of survivors (8 studies for T3; standardized mean difference (SMD) 1.16; 95% CI, 0.41-1.92; I2 = 97%; P < 0.01). Free thyroxine (FT4) levels in non-survivors were also lower than that of survivors (12 studies; SMD 0.54; 95% CI, 0.31-0.78; I2 = 83%; P < 0.01). There were no statistically significant differences in thyrotropin levels between non-survivors and survivors. NTIS was independently associated with increased risk of mortality in critically ill patients (odds ratio (OR) = 2.21, 95% CI, 1.64-2.97, I2 = 65% P < 0.01). The results favor the concept that decreased thyroid function might be associated with a worse outcome in critically ill patients. Hence, the measurement of TH could provide prognostic information on mortality in adult patients admitted to ICU.

A Case-Control Study on the Oxidative Balance of 50% Autologous Serum Eye Drops.

Importance. Autologous serum (AS) eye drops are recommended for severe dry eye in patients with ocular surface disease. No description of the antioxidant balance of AS eye drops has been reported in the literature. Objective. This study sought to evaluate the total reactive antioxidant potential (TRAP) and concentration of reactive oxygen species (ROS) in samples of 50% AS eye drops and their correlations with the demographic characteristics and lifestyle habits of patients with ocular surface disease and healthy controls. Design. This was a case-control study with a 3-month follow-up period. Participants. 16 patients with severe dry eye disease of different etiologies and 17 healthy controls matched by age, gender, and race were included. Results. TRAP and ROS were detected at all evaluated times. There were no differences in the mean ROS (p = 0.429) or TRAP (p = 0.475) levels between cases and controls. No statistically significant differences in the concentrations of ROS or TRAPs were found at 0, 15, or 30 days (p for ROS = 0.087 and p for TRAP = 0.93). Neither the demographic characteristics nor the lifestyle habits were correlated with the oxidative balance of the 50% AS eye drops. Conclusions and Relevance. Both fresh and frozen 50% AS eye drops present antioxidant capacities and ROS in an apparently stable balance. Moreover, patients with ocular surface disease and normal controls produce equivalent AS eye drops in terms of oxidative properties.