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Rheumatoid arthritis (RA) is an extremely painful autoimmune disease characterized by chronic joint inflammation leading to the erosion of adjacent cartilage and bone. Rheumatoid arthritis pathology is primarily driven by inappropriate infiltration and activation of immune cells within the synovium of the joint. There is no cure for RA. As such, manifestation of symptoms entails lifelong management via various therapies that aim to generally dampen the immune system or impede the function of immune mediators. However, these treatment strategies lead to adverse effects such as toxicity, general immunosuppression, and increased risk of infection. In pursuit of safer and more efficacious therapies, many emerging biomaterial-based strategies are being developed to improve payload delivery, specific targeting, and dose efficacy, and to mitigate adverse reactions and toxicity. In this review, we highlight biomaterial-based approaches that are currently under investigation to circumvent the limitations of conventional RA treatments.

RationalePulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females.ObjectiveTo evaluate whether and how Treg deficiency differentially affects male and female rats in experimental PH.Methods and resultsMale and female athymic rnu/rnu rats, lacking Tregs, were treated with the VEGFR2 (vascular endothelial growth factor receptor 2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution before SU5416 administration. Plasma PGI2 (prostacyclin) levels were measured. Lung and right ventricles were assessed for the expression of the vasoprotective proteins COX-2 (cyclooxygenase 2), PTGIS (prostacyclin synthase), PDL-1 (programmed death ligand 1), and HO-1 (heme oxygenase 1). Inhibitors of these pathways were administered to athymic rats undergoing Treg immune reconstitution. Finally, human cardiac microvascular endothelial cells cocultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and ER (estrogen receptor) expression, and culture supernatants were assayed for PGI2 and IL (interleukin)-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented right ventricular fibrosis, lower plasma PGI2 levels, decreased lung COX-2, PTGIS, HO-1, and PDL-1 expression and reduced right ventricular PDL-1 levels. In both sexes, Treg immune reconstitution protected against PH development and raised levels of plasma PGI2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and PD-1 (programmed death 1)/PDL-1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL-1, HO-1, ERs and increased supernatant levels of PGI2 and IL-10.ConclusionsIn 2 animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on the normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.

Autoimmunity, allergy, and transplant rejection are a collection of chronic diseases that are currently incurable, drastically decrease patient quality of life, and consume considerable health care resources. Underlying each of these diseases is a dysregulated immune system that results in the mounting of an inflammatory response against self or an innocuous antigen. As a consequence, afflicted patients are required to adhere to lifelong regimens of multiple immunomodulatory drugs to control disease and reclaim agency. Unfortunately, current immunomodulatory drugs are associated with a myriad of side effects and adverse events, such as increased risk of cancer and increased risk of serious infection, which negatively impacts patient adherence rates and quality of life. The field of immunoengineering is a new discipline that aims to harness endogenous biological pathways to thwart disease and minimize side effects using novel biomaterial-based strategies. We highlight and discuss polymeric micro/nanoparticles with inherent immunomodulatory properties that are currently under investigation in biomaterial-based therapies for treatment of autoimmunity, allergy, and transplant rejection. [ABSTRACT FROM AUTHOR]

Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor 1[alpha] (HIF-1[alpha]), but a reduction of HIF-2[alpha] protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif2[alpha] exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2[alpha] caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2[alpha] is an important mediator of lymphatic health. HIF-2[alpha] promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (AngptT) gene therapy. Our study suggests that HIF-2[alpha] normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2[alpha] pathways in lymphedema could mitigate long-term pathology and disability., Introduction Lymphedema is characterized by a chronic state of lymphatic vascular insufficiency with interstitial edema, inflammation, and dermal pathology; it affects 100-250 million individuals globally, but lacks effective pharmacological therapies [...]

The article discusses the acquired lymphedema as a cancer sequela and a global health problem that lacks pharmacologic therapy. It cites on the demonstration of ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase effectively reverses histopathology in lymphedema. The article also discusses the rise of lymphatic fluid during the lymphedema progression initial prolymphangiogenic concentrations.

A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts. [ABSTRACT FROM AUTHOR]

Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor 1 a (HIF-1a), but a reduction of HIF-2a protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif2a exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2a caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2a is an important mediator of lymphatic health. HIF-2a promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopo TIN-1 (Angpt1) gene therapy. Our study suggests that HIF-2a normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2a pathways in lymphedema could mitigate long-term pathology and disability. [ABSTRACT FROM AUTHOR]

A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts., (© 2015 American Heart Association, Inc.)