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Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.

Purpose of Review: Racial disparities appear to exist in the susceptibility and severity of systemic sclerosis (SSc, scleroderma) and are responsible for a greater health burden in blacks as compared with whites. Disparities in socioeconomic status and access to healthcare do not sufficiently explain the observed differences in prevalence and mortality. It is important to determine whether there might be a biologic basis for the racial disparities observed in SSc., Recent Findings: We present data to suggest that the increased susceptibility and severity of SSc in blacks may result in part from an imbalance of profibrotic and antifibrotic factors. Racial differences in the expression of transforming growth factor-β1 (TGF-β1) and caveolin-1, as well as differences in the expression of hepatocyte growth factor and PPAR-γ, have been demonstrated in blacks with SSc, as well as in normal black individuals. A genetic predisposition to fibrosis may account for much of the racial disparities between black and white patients with SSc., Summary: A better understanding of the biologic basis for the racial disparities observed in SSc may lead to improved therapies, along with the recognition that different therapies may need to be adapted for different groups of patients.

Background: Hepatopulmonary syndrome is a pulmonary vascular complication of cirrhosis in which intrapulmonary vasodilatation (IPV) results in hypoxemia. Endothelin-1 (ET-1), produced by proliferating cholangiocytes, has been identified as a mediator of IPV in an animal model of HPS, but the pathophysiology of IPV in humans has not been defined., Aim: The purpose of this study was to assess whether cirrhosis with IPV, which often leads to HPS, is associated with increased hepatic venous ET-1 blood levels., Methods: We performed a prospective cohort pilot study of 40 patients with liver disease undergoing transjugular liver biopsy from November 1, 2008 to September 1, 2009. Patients were categorized according to absence (-) or presence (+) of IPV as determined by bubble-contrasted echocardiography. Hepatic venous blood was assayed for ET-1 by ELISA. The percent volume of cholangiocytes in the liver biopsy specimen was determined by morphometric analysis, as a measure of bile duct proliferation., Results: Nine subjects were excluded, due to absence of cirrhosis (6) and patent foramen ovale (3). Of the remaining 31 subjects, IPV was present in 18 (58%). Median hepatic venous ET-1 was higher with IPV+ than IPV- at levels of 9.1 pg/mL (range 7.5-11.7) versus 2.1 pg/mL (1.3-5.6), respectively (P = 0.004). ET-1 levels correlated positively with cholangiocyte percent volume (r = 0.72, P < 0.001) but not with measures of liver dysfunction (bilirubin, INR, MELD score, or hepatic venous pressure gradient)., Conclusion: In human cirrhosis, increased hepatic venous ET-1 is associated with IPV and increased hepatic cholangiocyte volume.

The vascular hypothesis for the pathogenesis of systemic sclerosis was perhaps Professor LeRoy's most important scientific contribution. One early and important consequence of vascular injury is the release of activated thrombin. In this manuscript we present our data and review the current understanding of the role played by thrombin in the process of fibrosis, particularly as it relates to scleroderma lung disease. Thrombin's cellular effects are intimately involved in promoting myofibroblast differentiation, endothelial cell activation, extracellular matrix protein deposition, and the induction of important profibrotic factors. Such studies confirm that thrombin is one of the major mediators in the development and progression of pulmonary fibrosis. Therefore, targeting the major receptor of thrombin, PAR-I, and its downstream signaling molecules may lead to novel therapeutic approaches for the management of scleroderma lung fibrosis. We are indebted to Dr LeRoy for his many contributions to the field of scleroderma, and for all that he did to stimulate our interest in these studies.