Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice

Podowski, Megan; Calvi, C.; Metzger, Shana; Misono, Kaori; Poonyagariyagorn, Hataya; Lopez-Mercado, Armando; Ku, Therese; Lauer, Thomas; McGrath‐Morrow, Sharon A.; Berger, Alan E.; Cheadle, Christopher; Tuder, Rubin M.; Dietz, Harry C.; Mitzner, Wayne; Wise, Robert A.; Neptune, Enid

doi:10.1172/jci46215

Cited by 116 publications

(101 citation statements)

References 73 publications

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“…retinoic acid), while initially required to promote re-differentiation and related reactivation of abnormal features, finally reverses the epithelial phenotype by affecting epigenetic modifications [41]. Finally, targeting TGF-β1 was able to decrease mesenchymal features in vitro, in line with previous studies where anti-TGF-β treatment was able to improve both airway pathology and emphysema [42].…”

Section: Discussionsupporting

confidence: 82%

Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition

Gohy¹,

Hupin²,

et al. 2015

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In chronic obstructive pulmonary disease (COPD), epithelial changes and subepithelial fibrosis are salient features in conducting airways. Epithelial-to-mesenchymal transition (EMT) has been recently suggested in COPD, but the mechanisms and relationship to peribronchial fibrosis remain unclear. We hypothesised that de-differentiation of the COPD respiratory epithelium through EMT could participate in airway fibrosis and thereby, in airway obstruction.Surgical lung tissue and primary broncho-epithelial cultures (in air-liquid interface (ALI)) from 104 patients were assessed for EMT markers. Cell cultures were also assayed for mesenchymal features and for the role of transforming growth factor (TGF)-β1.The bronchial epithelium from COPD patients showed increased vimentin and decreased ZO-1 and E-cadherin expression. Increased vimentin expression correlated with basement membrane thickening and airflow limitation. ALI broncho-epithelial cells from COPD patients also displayed EMT phenotype in up to 2 weeks of culture, were more spindle shaped and released more fibronectin. Targeting TGF-β1 during ALI differentiation prevented vimentin induction and fibronectin release.In COPD, the airway epithelium displays features of de-differentiation towards mesenchymal cells, which correlate with peribronchial fibrosis and airflow limitation, and which are partly due to a TGF-β1-driven epithelial reprogramming. @ERSpublications The COPD airway epithelium is programmed for mesenchymal transition via a TGF-β1-dependent process

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Section: Discussionsupporting

confidence: 82%

Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition

Gohy¹,

Hupin²,

et al. 2015

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“…Although several studies have shown that antagonism of angiotensin II signaling results in decreased TGF-b signaling in a variety of tissues, including kidney, lung, skeletal muscle, heart, and aorta (Shihab et al 1997;Sun et al 1998;Lavoie et al 2005;Habashi et al 2006;Yao et al 2006;Cohn et al 2007;Podowski et al 2012), the exact mechanism by which this occurs is not fully understood (Gibbons et al 1992;Stouffer and Owens 1992;Wolf et al 1993Wolf et al , 1999Kagami et al 1994;Lee et al 1995;Campbell and Katwa 1997;Fukuda et al 2000;Boffa et al 2003;Naito et al 2004;RodriguezVita et al 2005;Zhou et al 2006;Chen et al 2013). Suppression of excessive Erk1 and Erk2 MAPK activation with losartan or an inhibitor of MAPK kinase (MAPKK, also known as MEK) has been shown to normalize aortic architecture and aneurysm pathology in MFS mouse models (Habashi et al 2011), indicating that Erk MAPK activation is critical to aneurysm progression.…”

Section: Tgf-b Family Signaling In Connective Tissuesmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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“…Morphometric studies were performed as previously described (19,20) on mice exposed to O2 for 4 days. Further details are provided in the online supplement Immunohistochemistry Immunohistochemistry (IHC) was performed as previously described (20).…”

Section: Morphometrymentioning

confidence: 99%

Superoxide Dismutase 3 Dysregulation in a Murine Model of Neonatal Lung Injury

Poonyagariyagorn

Metzger

Dikeman

et al. 2014

Am J Respir Cell Mol Biol

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Bronchopulmonary dysplasia (BPD), a common chronic respiratory disease that occurs after premature birth, is believed to be secondary to oxidative damage from hyperoxia and inflammation, which leads to impaired alveolar formation and chronic lung dysfunction. We hypothesized that extracellular superoxide dismutase (SOD)3, an antioxidant uniquely targeted to the extracellular matrix (ECM) and alveolar fluid, might have a different response (downregulation) to hyperoxic injury and recovery in room air (RA), thereby contributing to the persistent airspace injury and inflammation. We used a murine BPD model using postnatal hyperoxia (O2) (4 or 5 d) followed by short-term recovery (14 d) in RA, which mimics the durable effects after injury during alveolar development. This was associated with significantly increased mRNA expression for antioxidant genes mediated by nuclear factor erythroid 2-related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was significantly reduced in the O2-exposed mice compared with RA. Immunohistochemistry revealed decreased and disrupted SOD3 deposition in the alveolar ECM of O2-exposed mice. Furthermore, this distinct hyperoxic antioxidant and injury profile was reproducible in murine lung epithelial 12 cells exposed to O2.Overexpression of SOD3 rescued the injury measures in the O2-exposed cells. We establish that reduced SOD3 expression correlates with alveolar injury measures in the recovered neonatal hyperoxic lung, and SOD3 overexpression attenuates hyperoxic injury in an alveolar epithelial cell line. Such findings suggest a candidate mechanism for the pathogenesis of BPD that may lead to targeted interventions.

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Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice

Cited by 116 publications

References 73 publications

Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition

Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Superoxide Dismutase 3 Dysregulation in a Murine Model of Neonatal Lung Injury

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