Smooth Muscle Cells Relay Acute Pulmonary Inflammation via Distinct ADAM17/ErbB Axes

Dreymueller, Daniela; Martin, Christian; Schumacher, Jöerg; Groth, Esther; Boehm, Julia Katharina; Reiss, Lucy Kathleen; Uhlig, Stefan; Ludwig, Andreas

doi:10.4049/jimmunol.1302496

Cited by 24 publications

(25 citation statements)

References 34 publications

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“…More recently, VERGADI et al [2] provided evidence that not only alveolar macrophages are associated with chronic hypoxia-induced PH development in vivo, but that hypoxic alveolar macrophages are also able to induce PA-SMC proliferation in vitro. Conversely, PA-SMCs are known to release a large variety of pro-inflammatory factors including cytokines, chemokines and growth factors in asthma [41] and in acute lung inflammation [42]. Taken together, all these findings suggest that PA-SMC proliferation and perivascular monocyte/macrophage lineage cell accumulation may not represent two distinct components of the pulmonary vascular remodelling but rather two closely interdependent processes.…”

Section: Discussionmentioning

confidence: 50%

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Huertas

Thuillet

et al. 2015

Eur Respir J

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Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ⩽5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH ( pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH. @ERSpublications Targeting Ob/ObR-b axis represents an important tool for anti-proliferative and antiinflammatory strategies in PH http://ow.ly/I00jh

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Section: Discussionmentioning

confidence: 50%

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Huertas

Thuillet

et al. 2015

Eur Respir J

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“…The LPS-induced response was explained by ADAM17-mediated shedding of TGF-␣ and subsequent transactivation of SMCs via EGFR, leading to enhanced cytokine induction. The acid-induced response, however, was mediated by the release of neuregulins and ErbB4 transactivation (33). These findings do not only indicate an important role of lung interstitial cells in the transmission of inflammatory signals across the airways, but they also demonstrate that this process is governed by ADAM17.…”

Section: Adam17mentioning

confidence: 51%

“…This concept is supported by in vivo and in vitro experiments on the role of ADAM17 for inflammatory mediator production by SMCs. Mice lacking ADAM17 in SMCs (driven by Tagln-Cre) showed considerably decreased lung damage, edema formation, neutrophil recruitment, and cytokine production in response to intranasal LPS challenge (33). Moreover, these mice were also protected in a model of acid-induced lung inflammation.…”

Section: Adam17mentioning

confidence: 77%

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ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

Dreymueller

Uhlig

Ludwig

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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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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“…99 In lung interstitial smooth muscle cells, EGFR transactivation mediated by ADAM17-dependent shedding of ligands ( Fig 1 ) is necessary for the development of acute pulmonary infl ammatory responses, such as edema formation and neutrophil recruitment. 100 …”

Section: Human Egfrsmentioning

confidence: 99%

Matrix Metalloproteinases and Protein Tyrosine Kinases

Aschner

Zemans

Yamashita

et al. 2014

CHEST

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Acute lung injury (ALI) and ARDS fall within a spectrum of pulmonary disease that is characterized by hypoxemia, noncardiogenic pulmonary edema, and dysregulated and excessive infl ammation. While mortality rates have improved with the advent of specialized ICUs and lung protective mechanical ventilation strategies, few other therapies have proven eff ective in the management of ARDS, which remains a signifi cant clinical problem. Further development of biomarkers of disease severity, response to therapy, and prognosis is urgently needed.Several novel pathways have been identifi ed and studied with respect to the pathogenesis of ALI and ARDS that show promise in bridging some of these gaps. This review will focus on the roles of matrix metalloproteinases and protein tyrosine kinases in the pathobiology of ALI in humans, and in animal models and in vitro studies. These molecules can act independently, as well as coordinately, in a feed-forward manner via activation of tyrosine kinase-regulated pathways that are pivotal in the development of ARDS. Specifi c signaling events involving proteolytic processing by matrix metalloproteinases that contribute to ALI, including cytokine and chemokine activation and release, neutrophil recruitment, transmigration and activation, and disruption of the intact alveolar-capillary barrier, will be explored in the context of these novel molecular pathways.CHEST 2014; 146 (4): 1081 -1091 ABBREVIATIONS : ALI 5 acute lung injury ; ECM 5 extracellular matrix ; EGFR 5 epidermal growth factor receptor ; LPS 5 lipopolysaccharide ; MMP 5 matrix metalloproteinase ; NRTK 5 nonreceptor tyrosine kinase ; PDGF 5 platelet-derived growth factor ; PDGFR 5 platelet-derived growth factor receptor ; PTK 5 protein tyrosine kinase ; RTK 5 receptor tyrosine kinase ; SFK 5 Src family kinase ; VEGF 5 vascular endothelial growth factor ; VEGFR 5 vascular endothelial growth factor receptor ; VILI 5 ventilatorinduced lung injury Manuscript

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Smooth Muscle Cells Relay Acute Pulmonary Inflammation via Distinct ADAM17/ErbB Axes

Cited by 24 publications

References 34 publications

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Leptin signalling system as a target for pulmonary arterial hypertension therapy

ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

Matrix Metalloproteinases and Protein Tyrosine Kinases

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