Death at the airway epithelium in asthma

Lambrecht, Bart N.; Hammad, Hamida

doi:10.1038/cr.2013.26

Cited by 26 publications

(16 citation statements)

References 11 publications

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“…Chronic inflammation is thought to initiate and perpetuate cycles of tissue injury and repair in asthma, although remodeling may also occur in parallel with inflammation. In recent years, a significant body of information on a close relationship between epithelial inflammation and airway remodeling has emerged showing that chronic injury or defective repair of the bronchial and alveolar epithelium results in its persistent activation, with consequent chronic secretion of a variety of proinflammatory cytokines and growth factors that further drive chronic inflammation and remodeling in the subepithelial compartments (11).…”

Section: Discussionmentioning

confidence: 99%

PRMT1 Upregulated by Epithelial Proinflammatory Cytokines Participates in COX2 Expression in Fibroblasts and Chronic Antigen-Induced Pulmonary Inflammation

Sun

Liu

Roth

et al. 2015

The Journal of Immunology

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Protein arginine methyltransferase (PRMT)1, methylating both histones and key cellular proteins, has emerged as a key regulator of various cellular processes. This study aimed to identify the mechanism that regulates PRMT1 in chronic Ag-induced pulmonary inflammation (AIPI) in the E3 rat asthma model. E3 rats were challenged with OVA for 1 or 8 wk to induce acute or chronic AIPI. Expression of mRNAs was detected by real-time quantitative PCR. PRMT1, TGF-β, COX2, and vascular endothelial growth factor protein expression in lung tissues was determined by immunohistochemistry staining and Western blotting. In the in vitro study, IL-4–stimulated lung epithelial cell (A549) medium (ISEM) with or without anti–TGF-β Ab was applied to human fibroblasts from lung (HFL1). The proliferation of HFL1 was determined by MTT. AMI-1 (pan-PRMT inhibitor) was administered intranasally to chronic AIPI rats to determine PRMT effects on asthmatic parameters. In lung tissue sections, PRMT1 expression was significantly upregulated, mainly in epithelial cells, in acute AIPI lungs, whereas it was significantly upregulated mainly in fibroblasts in chronic AIPI lungs. The in vitro study revealed that ISEM elevates PRMT1, COX2, and vascular endothelial growth factor expressions, and it promoted fibroblast proliferation. The application of anti–TGF-β Ab suppressed COX2 upregulation by ISEM. AMI-1 inhibited the expression of COX2 in TGF-β–stimulated cells. In the in vivo experiment, AMI-1 administered to AIPI rats reduced COX2 production and humoral immune response, and it abrogated mucus secretion and collagen generation. These findings suggested that TGF-β–induced PRMT1 expression participates in fibroblast proliferation and chronic airway inflammation in AIPI.

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Section: Discussionmentioning

confidence: 99%

PRMT1 Upregulated by Epithelial Proinflammatory Cytokines Participates in COX2 Expression in Fibroblasts and Chronic Antigen-Induced Pulmonary Inflammation

Sun

Liu

Roth

et al. 2015

The Journal of Immunology

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“…In general, the age‐associated senescence in organ systems and initiation or progression of a wide range of chronic diseases involves minor or major adaptations or alterations in the integrity of architecture (morphology), function (behavior), biochemical, bioenergetics, immunological (cell mediated or humoral or CMI‐HI), mechanical and physical properties in tissues/cells that alter the intra‐, extra‐cellular components including declines in oxygen consumption [4–9, 36–60]. Among age‐associated biological readjustments in tissues/organs, the sustained oxidative stress (sub‐clinical, unresolved inflammation) perhaps has the most adverse cumulative influence in immune and non‐immune cells (e.g., APCs, T and B cells, epithelium, endothelium, GCs) responses that would damage cellular components (e.g., membrane, cytoplasm, chromosome, mitochondria, ER, lysosome, Golgi apparatus) and related molecules (e.g., DNA/RNA, epigenetic modifications, enzymes, proteins, cytokines, lipids) in vertebrates, invertebrates and humans [4–9, 61–80]. Examples are the reported data that strongly suggest that continuous (chronic) up‐regulation of pro‐inflammatory mediators (e.g., TNF‐α, IL1β, COX‐2, iNOS) are due to redox imbalance that activates anti‐ inflammatory signals including NF‐kB, IL‐10, PGE2, IL‐5 in an attempts to terminate inflammatory conditions.…”

Section: Connecting Dots On Age‐associated Diseases and Cancer Biologymentioning

confidence: 99%

Is cancer a severe delayed hypersensitivity reaction and histamine a blueprint?

Khatami

2016

Clinical & Translational Med

172

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Longevity and accumulation of multiple context‐dependent signaling pathways of long‐standing inflammation (antigen‐load or oxidative stress) are the results of decreased/altered regulation of immunity and loss of control switch mechanisms that we defined as Yin and Yang of acute inflammation or immune surveillance. Chronic inflammation is initiated by immune disruptors‐induced progressive changes in physiology and function of susceptible host tissues that lead to increased immune suppression and multistep disease processes including carcinogenesis. The interrelated multiple hypotheses that are presented for the first time in this article are extension of author's earlier series of ‘accidental’ discoveries on the role of inflammation in developmental stages of immune dysfunction toward tumorigenesis and angiogenesis. Detailed analyses of data on chronic diseases suggest that nearly all age‐associated illnesses, generally categorized as ‘mild’ (e.g., increased allergies), ‘moderate’ (e.g., hypertension, colitis, gastritis, pancreatitis, emphysema) or ‘severe’ (e.g., accelerated neurodegenerative and autoimmune diseases or site‐specific cancers and metastasis) are variations of hypersensitivity responses of tissues that are manifested as different diseases in immune‐responsive or immune‐privileged tissues. Continuous release/presence of low level histamine (subclinical) in circulation could contribute to sustained oxidative stress and induction of ‘mild’ or ‘moderate’ or ‘severe’ (immune tsunami) immune disorders in susceptible tissues. Site‐specific cancers are proposed to be ‘severe’ (irreversible) forms of cumulative delayed hypersensitivity responses that would induce immunological chaos in favor of tissue growth in target tissues. Shared or special features of growth from fetus development into adulthood and aging processes and carcinogenesis are briefly compared with regard to energy requirements of highly complex function of Yin and Yang. Features of Yang (growth‐promoting) arm of acute inflammation during fetus and cancer growth will be compared for consuming low energy from glycolysis (Warburg effect). Growth of fetus and cancer cells under hypoxic conditions and impaired mitochondrial energy requirements of tissues including metabolism of essential branched amino acids (e.g., val, leu, isoleu) will be compared for proposing a working model for future systematic research on cancer biology, prevention and therapy. Presentation of a working model provides insightful clues into bioenergetics that are required for fetus growth (absence of external threat and lack of high energy‐demands of Yin events and parasite‐like survival in host), normal growth in adulthood (balance in Yin and Yang processes) or disease processes and carcinogenesis (loss of balance in Yin–Yang). Future studies require focusing on dynamics and promotion of natural/inherent balance between Yin (tumoricidal) and Yang (tumorigenic) of effective immunity that develop after birth. Lawless growth of cancerous cells and loss of cell contac...

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“…This is a recently described novel airway epithelial mechanism to clear dead cells and thus mitigate Th2 inflammation in asthma (Juncadella, et al, 2013; Lambrecht & Hammad, 2013). This suggests that at least in the case of Rac1, its inhibition could have potential adverse consequences in allergic asthma, further adding to the complex and interconnected role that Rho family GTPases play in lung health and disease (Henson & Bratton, 2013).…”

Section: Pulmonary Diseasementioning

confidence: 99%

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Yeganeh

Wiechec

Ande

et al. 2014

Pharmacology & Therapeutics

137

129

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The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer.

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Death at the airway epithelium in asthma

Cited by 26 publications

References 11 publications

PRMT1 Upregulated by Epithelial Proinflammatory Cytokines Participates in COX2 Expression in Fibroblasts and Chronic Antigen-Induced Pulmonary Inflammation

PRMT1 Upregulated by Epithelial Proinflammatory Cytokines Participates in COX2 Expression in Fibroblasts and Chronic Antigen-Induced Pulmonary Inflammation

Is cancer a severe delayed hypersensitivity reaction and histamine a blueprint?

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

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