WNT/β-catenin signaling is modulated by mechanical ventilation in an experimental model of acute lung injury

Villar, Jesús; Cabrera, Nuria E.; Casula, Milena; Valladares, Francisco; Flores, Carlos; López-Aguilar, Josefina; Blanch, Lluís; Zhang, Haibo; Kacmarek, Robert M.; Slutsky, Arthur S.

doi:10.1007/s00134-011-2234-0

Cited by 50 publications

(54 citation statements)

References 33 publications

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“…We have previously reported that ␤-catenin signaling is activated in the lung epithelium in response to neutrophil transmigration and plays a critical role in epithelial repair after inflammatory injury (72), and other reports corroborate this finding (17,64,75). In canonical Wnt/␤-catenin signaling, ␤-catenin translocates to the nucleus and binds to the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors, enhancing expression of specific target genes, many of which are involved in cell proliferation; hence, ␤-catenin signaling has been implicated in development, tumorigenesis, and tissue repair (12,52).…”

supporting

confidence: 61%

“…Indeed, ␤-catenin and the CCN proteins are known to be involved in tissue repair after injury in various organs, including the lung, where they have been implicated in limiting injury and/or promoting repair in acute lung injury (2,7,14,17,30,31,64) and COPD (37,75). However, the effects of CCN proteins may be context dependent because WISP1 may enhance ventilator-induced lung injury via augmentation of macrophage proinflammatory responses (42).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of β-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury

Zemans

McClendon

Aschner

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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supporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Role of β-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury

Zemans

McClendon

Aschner

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Wnt5A has also been shown to be significantly upregulated in UIP/IPF and to promote proliferation and prevent apoptosis in fibroblasts from patients with UIP/IPF (Vuga et al 2009). Its fibrogenic qualities are also demonstrated by its up-regulation in sarcoidosis (Levänen et al 2011), ventilator-induced pulmonary fibrosis (Villar, et al 2011), and liver fibrosis (Rashid et al 2012). Recent studies have demonstrated an increased expression of Wnt5A in smooth muscle cells in asthma and its necessity for TGF-β-induced production of ECM (Kumawat et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts

Newman

Sills

Hanrahan

et al. 2015

J Histochem Cytochem.

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The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF.

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“…There is a paucity of literature investigating whether CLP increases susceptibility to VILI. Many studies using rodent lungs "primed" by CLP do not use a control group, which would allow differentiation of the effects of sepsis from the effects of high V T (35,36).…”

Section: Discussionmentioning

confidence: 99%

Cecal ligation and puncture accelerates development of ventilator-induced lung injury

Yehya

Xin

Oquendo

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Sepsis is a leading cause of respiratory failure requiring mechanical ventilation, but the interaction between sepsis and ventilation is unclear. While prior studies demonstrated a priming role with endotoxin, actual septic animal models have yielded conflicting results regarding the role of preceding sepsis on development of subsequent ventilator-induced lung injury (VILI). Using a rat cecal ligation and puncture (CLP) model of sepsis and subsequent injurious ventilation, we sought to determine if sepsis affects development of VILI. Adult male Sprague-Dawley rats were subject to CLP or sham operation and, after 12 h, underwent injurious mechanical ventilation (tidal volume 30 ml/kg, positive end-expiratory pressure 0 cmH 2O) for either 0, 60, or 120 min. Biochemical and physiological measurements, as well as computed tomography, were used to assess injury at 0, 60, and 120 min of ventilation. Before ventilation, CLP rats had higher levels of alveolar neutrophils and interleukin-1␤. After 60 min of ventilation, CLP rats had worse injury as evidenced by increased alveolar inflammation, permeability, respiratory static compliance, edema, oxygenation, and computed tomography. By 120 min, CLP and sham rats had comparable levels of lung injury as assessed by many, but not all, of these metrics. CLP rats had an accelerated and worse loss of end-expiratory lung volume relative to sham, and consistently higher levels of alveolar interleukin-1␤. Loss of aeration and progression of edema was more pronounced in dependent lung regions. We conclude that CLP initiated pulmonary inflammation in rats, and accelerated the development of subsequent VILI.sepsis; acute lung injury NONPULMONARY SEPSIS IS A leading cause of acute respiratory distress syndrome (15); however, the etiology of the lung injury from sepsis is unclear. This is confounded by the fact that many septic patients with respiratory failure require mechanical ventilation, which itself causes injury from regional overdistension and cyclic reopening of atelectatic lung (22). This ventilator-induced lung injury (VILI) is characterized by epithelial (7, 9) and endothelial (12, 37) dysfunction, with barrier failure leading to alveolar flooding. Because sepsis and VILI share similar proinflammatory cytokine profiles (34), it is possible that an initial septic insult predisposes lungs for secondary injury from VILI.Characterization of potential interaction between sepsis and VILI requires appropriate animal models that both recapitulate the proinflammatory cascade seen in humans and allow for the testing of a priming septic insult on development of subsequent VILI. The cecal ligation and puncture (CLP) model and its variants (8) induce a systemic inflammatory response from a polymicrobial abdominal infection. CLP, unlike surrogates like endotoxin injection (31), recreates sepsis progression most similarly to humans, with comparable hemodynamic and inflammatory profiles (8).Exogenous endotoxin administration is well established to predispose lung to further injury (5, 39)...

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WNT/β-catenin signaling is modulated by mechanical ventilation in an experimental model of acute lung injury

Abstract: Our findings demonstrate that the WNT/β-catenin signaling pathway is modulated early during sepsis and ventilator-induced lung injury, suggesting that activation of this pathway could play an important role in both lung injury progression and repair.

Cited by 50 publications

References 33 publications

Role of β-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury

Role of β-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts

Cecal ligation and puncture accelerates development of ventilator-induced lung injury

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