Sarcoidosis is a systemic inflammatory disease characterized by non-necrotizing granulomas in involved organs, most commonly the lung. Description of patient characteristics in the Western United States is limited. Furthermore, blood-based measures that relate to clinical sarcoidosis phenotypes are lacking. We present an analysis of a prospective, longitudinal sarcoidosis cohort at a Northern Californian academic medical center.

INTRODUCTION:We sought to determine the effects of brief exposures to low concentrations of tobacco secondhand smoke (SHS) on arterial flow-mediated dilation (FMD, a nitric oxide-dependent measure of vascular endothelial function), in a controlled animal model never before exposed to smoke. In humans, SHS exposure for 30 min impairs FMD. It is important to gain a better understanding of the acute effects of exposure to SHS at low concentrations and for brief periods of time.METHODS:We measured changes in FMD in rats exposed to a range of real-world levels of SHS for durations of 30 min, 10 min, 1 min, and 4 breaths (roughly 15 s).RESULTS:We observed a dose-response relationship between SHS particle concentration over 30 min and post-exposure impairment of FMD, which was linear through the range typically encountered in smoky restaurants and then saturated at higher concentrations. One min of exposure to SHS at moderate concentrations was sufficient to impair FMD.CONCLUSIONS:Brief SHS exposure at real-world levels reversibly impairs FMD. Even 1 min of SHS exposure can cause reduction of endothelial function.

Previously, we demonstrated concordance in differentially expressed genes in sarcoidosis blood and lung, implicating shared dysfunction of specific immune pathways. In the present study, we hypothesised that expression levels of candidate genes in sarcoidosis blood could predict and track with disease outcomes longitudinally.We applied Ingenuity Pathway Analysis to a cross-sectional derivation microarray dataset (n=38) to identify canonical pathways and candidate genes associated with sarcoidosis. In a separate longitudinal sarcoidosis cohort (n=103), we serially measured 48 candidate gene transcripts, and assessed their relation to disease chronicity and severity.In the cross-sectional derivation study, pathway analysis showed upregulation of genes related to interferon signalling and the role of pattern recognition receptors, and downregulation of T-cell receptor (TCR) signalling pathways in sarcoidosis. In the longitudinal cohort, factor analysis confirmed coregulation of genes marking these pathways and identified CXCL9 as an additional candidate pathway. CXCL9 and TCR factors discriminated between chronicversusnonprogressive disease, and CXCL9 predicted disease outcomes longitudinally. Interferon factor was similarly increased in both disease phenotypes. Factors associated with lung function decline included decreased TCR factor and increased CXCL9.These findings demonstrate blood transcriptomic signatures reflecting TCR signalling and CXCL9 predict sarcoidosis chronicity and correlate with disease severity longitudinally.

Identification of serum proteins that track with disease course in sarcoidosis may have clinical and pathologic importance. We previously identified up-regulated transcripts for interferon-inducible chemokines CXCL9, and CXCL10, in blood of sarcoidosis patients compared to controls. The objective of this study was to determine whether proteins encoded by these transcripts were elevated in serum and identified patients with remitting vs. chronic progressive sarcoidosis longitudinally.

Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intramyocardial injection of BMCs from distinct donor individuals who are healthy. In contrast, autologous BMCs from individuals after MI are used for clinical trials. Using BMCs from donor mice after MI, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to donor mice after MI prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments and suggest potential strategies to improve the success of clinical autologous BMC therapy.