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Antibias training is increasingly identified as a strategy to reduce maternal health disparities. Evidence to guide this work is limited. We conducted a community-guided scoping review to characterize new antibias research. Four of 508 projects met our criteria: US-based, publicly funded, initiated from January 1, 2018 to June 30, 2022, and featuring an intervention to reduce bias or racism in maternal health care providers. Training was embedded in multicomponent interventions in 3 projects, limiting its evaluation as a stand-alone intervention. Major public funders have sponsored a few projects to advance antibias training research in maternal health. More support is needed to develop a rigorous and scalable evidence base.

Objective Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterized by variable clinical outcomes, activation of innate immune pattern-recognition receptors (PRRs), and accumulation of α-smooth muscle actin (α-SMA)-expressing myofibroblasts. The aim of this study was to identify an association between these entities and mitochondrial DNA (mtDNA), an endogenous ligand for the intracellular DNA-sensing PRRs Toll-like receptor 9 (TLR-9) and cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING), which has yet to be determined. Methods Human lung fibroblasts (HLFs) from normal donors and SSc-ILD explants were treated with synthetic CpG DNA and assayed for α-SMA expression and extracellular mtDNA using quantitative polymerase chain reaction for the human MT-ATP6 gene. Plasma MT-ATP6 concentrations were evaluated in 2 independent SSc-ILD cohorts and demographically matched controls. The ability of SSc-ILD and control plasma to induce TLR-9 and cGAS/STING activation was evaluated with commercially available HEK 293 reporter cells. Plasma concentrations of type I interferons (IFNs), interleukin-6 (IL-6), and oxidized DNA were measured using electrochemiluminescence and enzyme-linked immunosorbent assay-based methods. Extracellular vesicles (EVs) precipitated from plasma were evaluated for MT-ATP6 concentrations and proteomics via liquid chromatography mass spectrometry. Results Normal HLFs and SSc-ILD fibroblasts developed increased α-SMA expression and MT-ATP6 release following CpG stimulation. Plasma mtDNA concentrations were increased in the 2 SSc-ILD cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS/STING activation as well as type I IFN and IL-6 expression. Plasma mtDNA was not oxidized and was conveyed by EVs displaying a proteomics profile consistent with a multicellular origin. Conclusion These findings demonstrate a previously unrecognized connection between EV-encapsulated mtDNA, clinical outcomes, and intracellular DNA-sensing PRR activation in SSc-ILD. Further study of these interactions could catalyze novel mechanistic and therapeutic insights into SSc-ILD and related disorders.

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1–expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1’s receptor, deleted in colorectal carcinoma; and therapeutic α(1) adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1(+) macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α(1) adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1–driven adrenergic processes and introduced α(1) blockers as a potentially new fibrotic therapy.

Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the humanMT-ATP6gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations betweenMT-ATP6concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls,MT-ATP6concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessiveMT-ATP6concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease with a median survival of 3–5 years [1]. Its disease course is highly variable, as some patients experience rapid deterioration in lung function while others experience more gradual decline [2]. The development of acute exacerbation of IPF (AE-IPF), a highly lethal complication of unknown etiology, has been shown to accelerate disease progression [3]. Presently, there are no accepted biomarkers that predict clinical deterioration [4], thus indicating an important, unmet need in the management of this devastating disease. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Sakamoto reports grants from Japan Society for the Promotion of Science (JSPS), grants from the Satoshi Okamoto Memorial Foundation of Pulmonary Fibrosis, during the conduct of the study; grants from Pulmonary Fibrosis Foundation, grants from Eli Lilly Japan, grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr. Furukawa has nothing to disclose. Conflict of interest: Dr. Yamano has nothing to disclose. Conflict of interest: Dr. Kataoka has nothing to disclose. Conflict of interest: Dr. Teramachi has nothing to disclose. Conflict of interest: Ms. Walia has nothing to disclose. Conflict of interest: Dr. Suzuki has nothing to disclose. Conflict of interest: Dr. Inoue has nothing to disclose. Conflict of interest: Dr. Nakahara has nothing to disclose. Conflict of interest: Dr. Ryu reports grants from the Boehringer Ingelheim Discovery Award., outside the submitted work. Dr. Ryu reports grants from the Boehringer Ingelheim Discovery Award, outside the submitted work. Conflict of interest: Dr. Hashimoto has nothing to disclose. Conflict of interest: Dr. Kondoh reports personal fees from Asahi Kasei Pharma Corp., personal fees from Boehringer Ingelheim Co., Ltd., personal fees from Janssen Pharmaceutical K.K., personal fees from Eisai inc., personal fees from KYORIN Pharmaceutical Co., Ltd., personal fees from Mitsubishi Tanabe Pharma, personal fees from Novartis Pharma K.K., personal fees from Shionogi & Co., outside the submitted work

Background: The pathogenesis of scleroderma associated interstitial lung disease (SSc-ILD) involves the uncontrolled differentiation of normal human lung fibroblasts (NHLFs) to alpha-smooth muscle actin (αSMA) expressing myofibroblasts mediated by transforming growth factor-β1 (TGF-β1). SSc-ILD has a highly variable clinical trajectory as some patients experience rapid deterioration in their ventilatory function while others remain stable. The association between the toll-like receptor 9 (TLR9) ligand mitochondrial DNA (mtDNA) and fibroblast activation and clinical outcomes in SSc-ILD has yet to be explored. Methods: NHLFs grown in the absence and presence of TGFβ1, CpG DNA, and chloroquine were assayed for αSMA expression and extracellular mtDNA release using qPCR for the human MT-ATP6 gene. This approach was then used to detect plasma mtDNA concentrations in two SSc-ILD cohorts, Boston and Yale, and demographically matched controls. TLR9 activation was quantified using commercially available human TLR9-expressing HEK 293 cells. Isolation of extracellular vesicles (EVs) were performed in the plasma from controls and Yale SSc-ILD subjects, and EVs were analyzed for mtDNA content and proteomics via mass spectrometry. Findings: TLR9 activity modulates αSMA expression and extracellular mtDNA release. Plasma mtDNA concentrations are increased in two independent SSc-ILD cohorts and activates TLR9. Longitudinal analysis reveals that plasma mtDNA predicts ventilatory decline and is cargoed by EVs. Proteomic analysis reveals a multicellular origin of EVs that involves cellular pathways that could act as mediators of the SSc-ILD state. Interpretation: These findings demonstrate an unrecognized connection with TLR9 activation mediated by extravesicular mtDNA and myofibroblast differentiation and clinical outcomes in SSc-ILD. Further study into the interactions between TLR9 and mtDNA could lead to novel mechanistic and therapeutic insights in this difficult to manage disease. Funding Statement: Parker B. Francis Foundation, Foundation for Sarcoidosis Research, Scleroderma Foundation, American Thoracic Society, National Institutes of Health, Gabriel and Alma Elias Research Fund, and Greenfield Foundation. Declaration of Interests: The authors have no relevant conflicts of interest to disclose. Ethical Approval Statement: All human studies were performed with informed consent on protocols approved by the Institutional Review Board at each institution.