epidermal-growth-factor and Airway-Remodeling

Amphiregulin is a member of epidermal growth factor family, and is also one of the ligand of epidermal growth factor receptor, it participates in many physiological and pathological process by combining with EGFR. Researches have proved that AREG participates in asthma and airway inflammatory diseases caused by smoking and PM 2.5, and AREG plays an important role in the process of airway remodeling and inflammation. This paper mainly reviews the expression and function of AREG, and focus on it's research status in airway inflammatory disease.

Topics: Airway Remodeling; Amphiregulin; Asthma; Epidermal Growth Factor; ErbB Receptors; Glycoproteins; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Smoking

The airway epithelium of cigarette smokers undergoes dramatic remodeling with hyperplasia of basal cells (BC) and mucus-producing cells, squamous metaplasia, altered ciliated cell differentiation and decreased junctional barrier integrity, relevant to chronic obstructive pulmonary disease and lung cancer. In this study, we show that epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) is induced by smoking in human airway epithelium as a result of epidermal growth factor (EGF)-driven squamous differentiation of airway BC stem/progenitor cells. In turn, AREG induced a unique EGFR activation pattern in human airway BC, distinct from that evoked by EGF, leading to BC- and mucous hyperplasia, altered ciliated cell differentiation and impaired barrier integrity. Further, AREG promoted its own expression and suppressed expression of EGF, establishing an autonomous self-amplifying signaling loop in airway BC relevant for promotion of EGF-independent hyperplastic phenotypes. Thus, EGF-AREG interplay in airway BC stem/progenitor cells is one of the mechanisms that mediates the interconnected pathogenesis of all major smoking-induced lesions in the human airway epithelium. Stem Cells 2017;35:824-837.

Topics: Adult; Airway Remodeling; Amphiregulin; Cell Differentiation; Cell Proliferation; Cilia; Down-Regulation; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Hyperplasia; Male; Respiratory Mucosa; Smoking; Stem Cells; Up-Regulation

Limited in vivo models exist to investigate the lung airway epithelial role in repair, regeneration, and pathology of chronic lung diseases. Herein, we introduce a novel animal model in asthma-a xenograft system integrating a differentiating human asthmatic airway epithelium with an actively remodeling rodent mesenchyme in an immunocompromised murine host. Human asthmatic and nonasthmatic airway epithelial cells were seeded into decellularized rat tracheas. Tracheas were ligated to a sterile cassette and implanted subcutaneously in the flanks of nude mice. Grafts were harvested at 2, 4, or 6 weeks for tissue histology, fibrillar collagen, and transforming growth factor-β activation analysis. We compared immunostaining in these xenografts to human lungs. Grafted epithelial cells generated a differentiated epithelium containing basal, ciliated, and mucus-expressing cells. By 4 weeks postengraftment, asthmatic epithelia showed decreased numbers of ciliated cells and decreased E-cadherin expression compared with nonasthmatic grafts, similar to human lungs. Grafts seeded with asthmatic epithelial cells had three times more fibrillar collagen and induction of transforming growth factor-β isoforms at 6 weeks postengraftment compared with nonasthmatic grafts. Asthmatic epithelium alone is sufficient to drive aberrant mesenchymal remodeling with fibrillar collagen deposition in asthmatic xenografts. Moreover, this xenograft system represents an advance over current asthma models in that it permits direct assessment of the epithelial-mesenchymal trophic unit.

Topics: Adult; Airway Remodeling; Animals; Asthma; Demography; Disease Models, Animal; Epidermal Growth Factor; Extracellular Matrix; Female; Heterografts; Humans; Lung; Male; Middle Aged; Pulmonary Fibrosis; Rats, Inbred F344; Signal Transduction; Tissue Donors; Transforming Growth Factor beta1; Young Adult

The concept of permanent narrowing of the airways resulting from chronic inflammation and fibrosis is called remodeling and is a common feature of asthma and chronic obstructive pulmonary disease (COPD). The eicosanoid contractile agents thromboxane A(2) (TxA(2)) and cysteinyl-leukotriene D(4) (LTD(4)) are among the recognized mitogens for human airway smooth muscle (ASM) cells. Statins are known to possess anti-inflammatory and immunomodulatory properties that are independent on their cholesterol-lowering effects and may result in clinical lung benefits. Rosuvastatin is the last agent of the lipid-lowering drugs to be introduced and experimental evidence indicates that it possess favorable pleiotropic effects in the cardiovascular and nervous systems. Yet, no data is available in the literature regarding its effects on human airway remodeling. The present study was aimed at examining the effect of rosuvastatin and the involvement of prenylated proteins in the response of human ASM cells to serum, epidermal growth factor (EGF) and eicosanoid contractile mitogens that activate TxA(2) prostanoid and LTD(4) receptors.. Cell growth was assessed by nuclear incorporation of [(3)H]thymidine in human ASM cells serum-starved and then stimulated for 48 h in MEM plus 0.1% BSA containing mitogens in the absence and presence of modulators of the mevalonate and prenylation pathways.. We found that rosuvastatin dose-dependently inhibited serum-, EGF-, the TxA(2) stable analog U46619-, and LTD(4)-induced human ASM cells growth. All these effects were prevented by pretreatment with mevalonate. Addition of the prenylation substrates farnesol and geranylgeraniol reversed the effect of rosuvastatin on EGF and U46619, respectively. Interestingly, only mevalonate showed restoration of cell growth following rosuvastatin treatment in LTD(4) and LTD(4) plus EGF treated cells, suggesting a possible involvement of both farnesylated and geranylgeranylated proteins in the cysteinyl-LT-induced cell growth.. The hydrophilic statin rosuvastatin exerts direct effects on human ASM cells mitogenic response in vitro by inhibiting prenylation of signaling proteins, likely small G proteins. These findings are consistent with previous observed involvement of small GTPase signaling in EGF- and U46619-induced human airway proliferation and corroborate the recent interest in the potential clinical benefits of statins in asthma/COPD.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Remodeling; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Eicosanoids; Epidermal Growth Factor; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukotriene D4; Mevalonic Acid; Mitogens; Myocytes, Smooth Muscle; Pyrimidines; Receptors, Leukotriene; Rosuvastatin Calcium; Serum Albumin, Bovine; Signal Transduction; Sulfonamides

Topics: Adrenal Cortex Hormones; Adrenergic alpha-2 Receptor Agonists; Adult; Aged; Aged, 80 and over; Airway Obstruction; Airway Remodeling; Asthma; Chronic Disease; Elasticity; Epidermal Growth Factor; Female; Follow-Up Studies; Humans; Leukotriene Antagonists; Lung; Male; Middle Aged; Muscarinic Antagonists; Prospective Studies; Pulmonary Emphysema; Radiography