Persistent microbial infections and idiopathic pulmonary fibrosis - an insight into pathogenesis.

Interstitial lung disease (ILD) is characterized by chronic inflammation and scarring of the lungs, of which idiopathic pulmonary fibrosis (IPF) is the most devastating pathologic form. Idiopathic pulmonary fibrosis pathogenesis leads to loss of lung function and eventual death in 50% of patients, making it the leading cause of ILD-associated mortality worldwide. Persistent and subclinical microbial infections are implicated in the acute exacerbation of chronic lung diseases.

Complement Immune System in Pulmonary Hypertension-Cooperating Roles of Circadian Rhythmicity in Complement-Mediated Vascular Pathology.

Originally discovered in the 1890s, the complement system has traditionally been viewed as a "compliment" to the body's innate and adaptive immune response. However, emerging data have shown that the complement system is a much more complex mechanism within the body involved in regulating inflammation, gene transcription, attraction of macrophages, and many more processes. Sustained complement activation contributes to autoimmunity and chronic inflammation.

Alternative adenosine Receptor activation: The netrin-Adora2b link.

During hypoxia or inflammation, extracellular adenosine levels are elevated. Studies using pharmacologic approaches or genetic animal models pertinent to extracellular adenosine signaling implicate this pathway in attenuating hypoxia-associated inflammation. There are four distinct adenosine receptors.

SARS-CoV-2 Infection: Host Response, Immunity, and Therapeutic Targets.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in a global pandemic with severe socioeconomic effects. Immunopathogenesis of COVID-19 leads to acute respiratory distress syndrome (ARDS) and organ failure. Binding of SARS-CoV-2 spike protein to human angiotensin-converting enzyme 2 (hACE2) on bronchiolar and alveolar epithelial cells triggers host inflammatory pathways that lead to pathophysiological changes.

Neuroprotective Effects of Stem Extract in Transgenic Mice Overexpressing Amyloid Precursor Protein.

To mimic Alzheimer's disease, transgenic mice overexpressing the amyloid precursor protein (APP) were used in this study. We hypothesize that the neuroprotective effects of ETAS®50, a standardized extract of stem produced by Amino Up Co., Ltd.

Allogeneic Bone Marrow-Derived Mesenchymal Stem Cell Safety in Idiopathic Parkinson's Disease.

Background: Neuroinflammation plays a key role in PD pathogenesis, and allogeneic bone marrow-derived mesenchymal stem cells can be used as an immunomodulatory therapy.

Objective: The objective of this study was to prove the safety and tolerability of intravenous allogeneic bone marrow-derived mesenchymal stem cells in PD patients.

Methods: This was a 12-month single-center open-label dose-escalation phase 1 study of 20 subjects with mild/moderate PD assigned to a single intravenous infusion of 1 of 4 doses: 1, 3, 6, or 10 × 10 allogeneic bone marrow-derived mesenchymal stem cells/kg, evaluated 3, 12, 24, and 52 weeks postinfusion.

Development of pulmonary fibrosis after heart failure induced by elevated left atrial pressure.

Background: Chronic heart failure (CHF) is a common and serious complication of patients with ischemic heart disease that may eventually lead to the development of pulmonary fibrosis. While other forms of pulmonary fibrosis have been studied extensively, little is known about the mechanisms that lead to heart failure associated with pulmonary fibrosis. The purpose of our study was to develop a rat pulmonary edema/fibrosis model induced by chronically elevated left atrial pressure (LAP), simulating CHF pathophysiology.

Identification of Fibrinogen as a Key Anti-Apoptotic Factor in Human Fresh Frozen Plasma for Protecting Endothelial Cells In Vitro.

Resuscitation with human fresh frozen plasma (FFP) in hemorrhagic shock (HS) patients is associated with improved clinical outcomes. Our group has demonstrated that the beneficial effect of FFP is due to its blockade on endothelial hyperpermeability, thereby improving vascular barrier function. The current study aimed to investigate HS-induced endothelial cell apoptosis, a potential major contributor to the endothelial hyperpermeability, and to determine the effect and the key components/factors of FFP on protecting endothelial cells from apoptosis.

Thromboelastographic assessment of the impact of mexiletine on coagulation abnormalities induced by air or normal saline intravenous injections in conscious rats.

Background: Thromboelastography (TEG) in venous air embolism (VAE) has been poorly studied. We induced coagulation abnormalities by VAE in a rat model, assessed by TEG with and without mexiletine, a lidocaine analogue local anesthetic.

Methods: Twenty-three Sprague Dawley rats instrumented under isoflurane anesthesia and allowed to recover five days prior to the experiments were randomized into three experimental groups: 1) VAE (n = 6); 2) VAE and mexiletine (n = 9); and 3) normal saline (NS) alone (control group, n = 8).

Are Temporal Differences in GDNF and NOS Isoform Induction Contributors to Neurodegeneration? A Fluorescence Microscopy-Based Study.

Background: Specific factors in Parkinson's disease have become targets as to their protective and degenerative effects. We have demonstrated that cytokines and PD-CSF detrimentally affect microglia and astrocyte growth. While glial cell-derived neurotrophic factor (GDNF) has been recognized as a possible neuron-rescue agent, nitric oxide synthase (NOS) has been implicated in neurodegenerative processes.

Active hexose correlated compound modulates LPS-induced hypotension and gut injury in rats.

We hypothesized that AHCC; (Amino UP Chemical Co., Ltd., Sapporo, Japan), a mushroom mycelium extract obtained from liquid culture of Lentinula edodes, restores immune function in LPS-induced inflammation in the gut, especially when the nitric oxide signaling pathway is impaired.

AHCC Activation and Selection of Human Lymphocytes via Genotypic and Phenotypic Changes to an Adherent Cell Type: A Possible Novel Mechanism of T Cell Activation.

Active Hexose Correlated Compound (AHCC) is a fermented mushroom extract and immune supplement that has been used to treat a wide range of health conditions. It helps in augmentation of the natural immune response and affects immune cell activation and outcomes. The goal of this project was to study and understand the role and mechanisms of AHCC supplementation in the prevention of immunosuppression through T cell activation.

Adiponectin in Fresh Frozen Plasma Contributes to Restoration of Vascular Barrier Function After Hemorrhagic Shock.

Hemorrhagic shock is the leading cause of preventable deaths in civilian and military trauma. Use of fresh frozen plasma (FFP) in patients requiring massive transfusion is associated with improved outcomes. FFP contains significant amounts of adiponectin, which is known to have vascular protective function.

Study of acute hemocoagulation changes in a porcine endotoxemic shock model using thrombelastography.

Disseminated intravascular coagulation and fibrinolysis have been associated with lipopolysaccharide (LPS)-induced endotoxemic sepsis. It has been well established by point-of-care (POC) thrombelastography (TEG) that pigs have a hemocoagulation pathophysiology that resembles humans. We evaluated the use of TEG during the development of coagulation abnormalities in a porcine model of endotoxemia.

Inflammatory cells and cytokines in the olfactory bulb of a rat model of neuroinflammation; insights into neurodegeneration?

This study examined inflammatory cell and cytokine production in brain tissue from a lipopolysaccharide (LPS)-treated rat model that mimics many of the neuropathologic changes associated with neurodegenerative diseases We also monitored the appearance of a glial cell line-derived neurotrophic factor (GDNF) and circulating nitric oxide (NO) levels, as well as an immune system-associated cells in a selected area of the brain, the olfactory lobe. The studies were based on the hypothesis that LPS treatment stimulates temporal changes within the brain and that these responses include immune cell recruitment, increased tissue levels of immune modulating cytokines and NO, as well as greater glial cell activation resulting in increased production of GDNF. As previously reported by other investigators, our animal model of systemic LPS treatment leads to an increase in the concentrations of circulating cytokines, including TNF-α, IL-Iβ, and IL-6, with a maximum response 6 h post LPS administration.

Lactoferrin moderates LPS-induced hypotensive response and gut injury in rats.

Hypotension is a physiologic state of low blood pressure, the causes of which range from dehydration to underlying serious medical disorders. The aim of this study was to assess the utility of lactoferrin (LF), a natural immunomodulator, to restrain LPS-induced hypotension in rats. LF has previously demonstrated a role in mediation of immune responses, including control of inflammatory cytokine production during acute inflammation.

Cobinamides are novel coactivators of nitric oxide receptor that target soluble guanylyl cyclase catalytic domain.

Soluble guanylyl cyclase (sGC), a ubiquitously expressed heme-containing receptor for nitric oxide (NO), is a key mediator of NO-dependent processes. In addition to NO, a number of synthetic compounds that target the heme-binding region of sGC and activate it in a NO-independent fashion have been described. We report here that dicyanocobinamide (CN2-Cbi), a naturally occurring intermediate of vitamin B(12) synthesis, acts as a sGC coactivator both in vitro and in intact cells.

Bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock.

Hemorrhagic shock (HS) and trauma is currently the leading cause of death in young adults worldwide. Morbidity and mortality after HS and trauma is often the result of multi-organ failure such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions with few therapeutic options. Bone marrow derived mesenchymal stem cells (MSCs) are a multipotent stem cell population that has shown therapeutic promise in numerous pre-clinical and clinical models of disease.

RNA splicing in regulation of nitric oxide receptor soluble guanylyl cyclase.

Soluble guanylyl cyclase (sGC) is a key protein in the nitric oxide (NO)/-cGMP signaling pathway. sGC activity is involved in a number of important physiological processes including smooth muscle relaxation, neurotransmission and platelet aggregation and adhesion. Regulation of sGC expression and activity emerges as a crucial factor in control of sGC function in normal and pathological conditions.

Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic shock are time dependent and diminish between days 0 and 5 after thaw.

Background: Clinical studies have shown that resuscitation with fresh frozen plasma (FFP) is associated with improved outcome after severe hemorrhagic shock (HS). We hypothesized that in addition to its effects on hemostasis, FFP has protective and stabilizing effects on the endothelium that translate into diminished endothelial cell (EC) permeability and improved resuscitation in vivo after HS. We further hypothesized that the beneficial effects of FFP would diminish over 5 days of routine storage at 4 degrees C.

Cytokines disrupt intracellular patterns of Parkinson's disease-associated proteins alpha-synuclein, tau and ubiquitin in cultured glial cells.

The purpose of this study was to determine the effects of specific proinflammatory cytokines interleukin-6 (Il-6), interleukin-1beta (Il-1beta), interferon-gamma (IFN), and tumor necrosis factor-alpha (TNFalpha), on content and distribution of alpha-synuclein (alpha-synuclein), tau and ubiquitin in human derived cultured glial cells. Exposure paradigms mimicked acute (2 h), intermediate (18 h) and prolonged time frames (96 h); consisting of single or repeated low doses (10 ng/ml) or high doses (50 ng/ml), consistent with either mild or serious systemic infectious/inflammatory responses. Images of intracellular protein content and distribution were reconstructed from emission patterns generated by fluorescence deconvolution microscopy.

Vascular system: role of nitric oxide in cardiovascular diseases.

In contrast with the short research history of the enzymatic synthesis of nitric oxide (NO), the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin) is the first compound of this category. On October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning NO as a signaling molecule in the cardiovascular system.

Distribution of NOS isoforms in a porcine endotoxin shock model.

Sepsis is a major cause of morbidity and mortality. NO, an endogenous vasodilator, has been associated with the hypotension, catecholamine hyporesponsiveness, and myocardial depression of septic shock. Although iNOS is thought to be responsible for the hypotension and loss of vascular tone occurring several hours after endotoxin administration, little is known on the effects of constitutive eNOS on LPS-induced organ dysfunction.