Strain-induced Differentiation of Fetal Type II Epithelial Cells Is Mediated via the Integrin α6β1-ADAM17/Tumor Necrosis Factor-α-converting Enzyme (TACE) Signaling Pathway

Wang, Yulian; Huang, Zheping; Nayak, Pritha S.; Matthews, Benjamin D.; Warburton, David; Shi, Wei; Sanchez‐Esteban, Juan

doi:10.1074/jbc.m113.473777

Cited by 25 publications

(17 citation statements)

References 58 publications

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“…Different in vitro ECM culture conditions have been shown to alter lung epithelial cell differentiation with laminins promoting a type II cell phenotype, and fibronectin and collagen I inducing type I cell characteristics (Isakson et al, 2001;Lwebuga-Mukasa, 1991;Olsen et al, 2005;Rannels and Rannels, 1989). In addition to the ECM type, physical force mediated through integrin-ECM interactions regulate lung epithelial cell differentiation in vitro through unknown mechanisms (Huang et al, 2012;Sanchez-Esteban et al, 2004;Wang et al, 2013Wang et al, , 2006Wang et al, , 2009. Thus, it is likely that abnormally differentiated type II cells in β1 SP-C.Cre mice result from impaired integrin-dependent attachment and altered interactions with the ECM.…”

Section: Discussionmentioning

confidence: 99%

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

et al. 2014

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Integrin-dependent interactions between cells and extracellular matrix regulate lung development; however, specific roles for β1-containing integrins in individual cell types, including epithelial cells, remain incompletely understood. In this study, the functional importance of β1 integrin in lung epithelium during mouse lung development was investigated by deleting the integrin from E10.5 onwards using surfactant protein C promoter-driven Cre. These mutant mice appeared normal at birth but failed to gain weight appropriately and died by 4 months of age with severe hypoxemia. Defects in airway branching morphogenesis in association with impaired epithelial cell adhesion and migration, as well as alveolarization defects and persistent macrophagemediated inflammation were identified. Using an inducible system to delete β1 integrin after completion of airway branching, we showed that alveolarization defects, characterized by disrupted secondary septation, abnormal alveolar epithelial cell differentiation, excessive collagen I and elastin deposition, and hypercellularity of the mesenchyme occurred independently of airway branching defects. By depleting macrophages using liposomal clodronate, we found that alveolarization defects were secondary to persistent alveolar inflammation. β1 integrin-deficient alveolar epithelial cells produced excessive monocyte chemoattractant protein 1 and reactive oxygen species, suggesting a direct role for β1 integrin in regulating alveolar homeostasis. Taken together, these studies define distinct functions of epithelial β1 integrin during both early and late lung development that affect airway branching morphogenesis, epithelial cell differentiation, alveolar septation and regulation of alveolar homeostasis.

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Section: Discussionmentioning

confidence: 99%

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

et al. 2014

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“…; Wang et al . ). None the less, such insights will be important due to the limited specificity of currently available pharmacological inhibitors of ADAM17, including the TAPI compounds used in our study, which can inhibit other ADAMs and matrix metalloproteases (Saftig & Reiss, ).…”

Section: Discussionmentioning

confidence: 97%

Hypercapnia attenuates ventilator‐induced lung injury via a disintegrin and metalloprotease‐17

Otulakowski

Engelberts

Gusarova

et al. 2014

The Journal of Physiology

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Key pointsr Hypercapnia is common in mechanically ventilated patients with lung injury; while CO 2 can ameliorate experimental lung injury, it can also cause harm.r Because hypercapnia can protect against ventilator-induced lung injury (VILI), understanding its impact on key signalling pathways may provide insight into the mechanisms of VILI.r We show that hypercapnia blocks stretch-mediated activation of p44/42 mitogen-activated protein kinase (MAPK) signalling in alveolar epithelial cells; this occurs through inhibition of sheddase (i.e. the metalloprotease, ADAM17), which releases ligands that bind to the epidermal growth factor receptor.r In vivo pharmacological blockade of ADAM17 reduces downstream MAPK activation and attenuates VILI in a two-hit mouse model. r Thus, hypercapnia uncovered a novel ADAM17-dependent mechanism of VILI, and this represents a potential therapeutic target.Abstract Hypercapnic acidosis, common in mechanically ventilated patients, has been reported to exert both beneficial and harmful effects in models of lung injury. Understanding its effects at the molecular level may provide insight into mechanisms of injury and protection. The aim of this study was to establish the effects of hypercapnic acidosis on mitogen-activated protein kinase (MAPK) activation, and determine the relevant signalling pathways. p44/42 MAPK activation in a murine model of ventilator-induced lung injury (VILI) correlated with injury and was reduced in hypercapnia. When cultured rat alveolar epithelial cells were subjected to cyclic stretch, activation of p44/42 MAPK was dependent on epidermal growth factor receptor (EGFR) activity and on shedding of EGFR ligands; exposure to 12% CO 2 without additional buffering blocked ligand shedding, as well as EGFR and p44/42 MAPK activation. The EGFR ligands are known substrates of the matrix metalloprotease ADAM17, suggesting stretch activates and hypercapnic acidosis blocks stretch-mediated activation of ADAM17. This was corroborated in the isolated perfused mouse lung, where elevated CO 2 also inhibited stretch-activated shedding of the ADAM17 substrate TNFR1 from airway epithelial cells. Finally, in vivo confirmation was obtained in a two-hit murine model of VILI where pharmacological inhibition of ADAM17 reduced both injury and p44/42 MAPK activation. Thus, ADAM17 is an important proximal mediator of VILI; its inhibition is one mechanism of hypercapnic protection and may be a target for clinical therapy.

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“…Lung epithelial knockout (driven by SPC-rTA/TetO-Cre) results in developmental defects, including reduced saccular formation and decreased proliferation and differentiation of mid-distal epithelium (211). In cultured fetal epithelial cells, mechanical strain was found to induce ADAM17 activity via its binding to ␣6␤1-integrin, leading to enhanced HB-EGF shedding and differentiation (199). In vitro findings on the transactivation of ErbB receptors via growth factor shedding suggest a number of potentially proinflammatory properties of ADAM17 that remain to be studied in more detail.…”

Section: Adam17mentioning

confidence: 99%

ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

Dreymueller

Uhlig

Ludwig

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

121

107

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-Acute and chronic lung inflammation is driven and controlled by several endogenous mediators that undergo proteolytic conversion from surface-expressed proteins to soluble variants by a disintegrin and metalloproteinase (ADAM)-family members. TNF and epidermal growth factor receptor ligands are just some of the many substrates by which these proteases regulate inflammatory or regenerative processes in the lung. ADAM10 and ADAM17 are the most prominent members of this protease family. They are constitutively expressed in most lung cells and, as recent research has shown, are the pivotal shedding enzymes mediating acute lung inflammation in a cell-specific manner. ADAM17 promotes endothelial and epithelial permeability, transendothelial leukocyte migration, and inflammatory mediator production by smooth muscle and epithelial cells. ADAM10 is critical for leukocyte migration and alveolar leukocyte recruitment. ADAM10 also promotes allergic asthma by driving B cell responses. Additionally, ADAM10 acts as a receptor for Staphylococcus aureus (S. aureus) ␣-toxin and is crucial for bacterial virulence. ADAM8, ADAM9, ADAM15, and ADAM33 are upregulated during acute or chronic lung inflammation, and recent functional or genetic analyses have linked them to disease development. Pharmacological inhibitors that allow us to locally or systemically target and differentiate ADAM-family members in the lung suppress acute and asthmatic inflammatory responses and S. aureus virulence. These promising results encourage further research to develop therapeutic strategies based on selected ADAMs. These studies need also to address the role of the ADAMs in repair and regeneration in the lung to identify further therapeutic opportunities and possible side effects. metalloproteinase; shedding; inflammation; edema; asthma ACUTE OR CHRONIC INFLAMMATION in the lung can lead to a fatal loss of lung functions. Acute inflammation resulting from infection, aspiration of gastric juice, or overventilation during intensive care is initially characterized by enhanced inflammatory mediator production, edema formation, and recruitment of innate immune cells with the risk of lung damage. Asthma, chronic obstructive pulmonary disease (COPD), and lung fibrosis are fatal chronic diseases that are driven by persistent inflammation with a lack of resolution and impaired tissue regeneration. Targeting the immune response is the underlying principle of many treatment strategies against these diseases (reviewed in Ref. 7).The cytokines, growth factors, receptors, and adhesion molecules that drive the inflammatory process are all under intensive scrutiny. Many of these molecules undergo functional modulation by limited proteolysis, bringing the participating proteases into the focus of attention. Among these proteases is a class of metalloproteinases that subdivides into the matrix metalloproteinases (MMP) and the families of a disintegrin and metalloproteinases (ADAM) and ADAM with trombospondin motif. MMPs have already been intensively investigated with resp...

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Strain-induced Differentiation of Fetal Type II Epithelial Cells Is Mediated via the Integrin α6β1-ADAM17/Tumor Necrosis Factor-α-converting Enzyme (TACE) Signaling Pathway

Cited by 25 publications

References 58 publications

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

Hypercapnia attenuates ventilator‐induced lung injury via a disintegrin and metalloprotease‐17

ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

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