Vardenafil Activity in Lung Fibrosis and In Vitro Synergy with Nintedanib

Bourne, Michael H.; Kottom, Theodore J.; Hebrink, Deanne; Choudhury, Malay; Leof, Edward B.; Limper, Andrew H.

doi:10.3390/cells10123502

Cited by 6 publications

(4 citation statements)

References 31 publications

(59 reference statements)

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“…Refs. 35 – 38 ). The appearance of the inflamed colon from NIN + TNBS-treated animals was similar to that of TNBS-treated animals, with both showing mucosal damage and an intense submucosal inflammatory infiltrate that extended into the circular and longitudinal smooth muscle layers (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nintedanib regulates intestinal smooth muscle hyperplasia and phenotype in vitro and in TNBS colitis in vivo

Kataria

Kerr

Lourenssen

et al. 2022

Sci Rep

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Chronic inflammation of the human intestine in Crohn’s disease (CD) causes bowel wall thickening, which typically progresses to stricturing and a recurrent need for surgery. Current therapies have limited success and CD remains idiopathic and incurable. Recent evidence shows a key role of intestinal smooth muscle cell (ISMC) hyperplasia in stricturing, which is not targeted by current anti-inflammatory therapeutics. However, progression of idiopathic pulmonary fibrosis, resembling CD in pathophysiology, is controlled by the tyrosine kinase inhibitors nintedanib (NIN) or pirfenidone, and we investigated these drugs for their effect on ISMC. In a culture model of rat ISMC, NIN inhibited serum- and PDGF-BB-stimulated growth and cell migration, and promoted the differentiated phenotype, while increasing secreted collagen. NIN did not affect signaling through PDGF-Rβ or NFκB but did inhibit cytokine-induced expression of the pro-inflammatory cytokines IL-1β and TNFα, supporting a transcriptional level of control. In TNBS-induced colitis in mice, which resembles CD, NIN decreased ISMC hyperplasia as well as expression of TNFα and IL-1β, without effect in control animals. NIN also inhibited growth of human ISMC in response to human serum or PDGF-BB, which further establishes a broad range of actions of NIN that support further trial in human IBD.

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Section: Resultsmentioning

confidence: 99%

Nintedanib regulates intestinal smooth muscle hyperplasia and phenotype in vitro and in TNBS colitis in vivo

Kataria

Kerr

Lourenssen

et al. 2022

Sci Rep

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show abstract

“…PF is a progressive interstitial lung disease characterized by acute early inflammation and evolutional fibrosis which result in pathological lung remodeling and respiratory remodeling and breathing failure 24 . Many studies confirm that PF is associated with ECM 25 , 26 . During the PF progress, many factors prompt the differentiation of fibroblasts into myofibroblasts in lung tissues, and lead to the high expressions of FN, α-SMA, Col 1A1 and Col 3A1 27 , 28 .…”

Section: Discussionmentioning

confidence: 97%

Inhibitory effects of Schisandrin C on collagen behavior in pulmonary fibrosis

Xu,

Zhao,

Song

et al. 2023

Sci Rep

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Pulmonary fibrosis (PF) is a serious progressive fibrotic disease that is characterized by excessive accumulation of extracellular matrix (ECM), thus resulting in stiff lung tissues. Lysyl oxidase (LOX) is an enzyme involved in fibrosis by catalyzing collagen cross-linking. Studies found that the ingredients in schisandra ameliorated bleomycin (BLM)-induced PF, but it is unknown whether the anti-PF of schisandra is related to LOX. In this study, we established models of PF including a mouse model stimulated by BLM and a HFL1 cell model induced by transforming growth factor (TGF)-β1 to evaluate the inhibition effects of Schisandrin C (Sch C) on PF. We observed that Sch C treatment decreased pulmonary indexes compared to control group. Treatment of Sch C showed a significant reduction in the accumulation of ECM as evidenced by decreased expressions of α-SMA, FN, MMP2, MMP9, TIMP1 and collagen proteins such as Col 1A1, and Col 3A1. In addition, the expression of LOX in the lung tissue of mice after Sch C treatment was effectively decreased compared with the MOD group. The inhibition effects in vitro were consistent with those in vivo. Mechanistic studies revealed that Sch C significantly inhibited TGF-β1/Smad2/3 and TNF-α/JNK signaling pathways. In conclusion, our data demonstrated that Sch C significantly ameliorated PF in vivo and vitro, which may play an important role by reducing ECM deposition and inhibiting the production of LOX.

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“…Many studies con rm that PF is associated with ECM 20,21 . During the PF progress, many factors prompt the differentiation of broblasts into myo broblasts in lung tissues, and lead to the high expressions of FN, α-SMA, Col 1A1 and Col 3A1 22,23 .…”

Section: Discussionmentioning

confidence: 99%

Sch C Ameliorates Pulmonary Fibrosis by Inhibiting the Level of LOX

Zhao

Song

et al. 2023

Preprint

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Pulmonary fibrosis (PF) is a serious progressive fibrotic disease that is characterized by excessive accumulation of extracellular matrix (ECM), thus resulting in stiff lung tissues. Lysyl oxidase (LOX) is an enzyme involved in fibrosis by catalyzing collagen cross-linking. Studies found that the ingredients in schisandra ameliorated bleomycin (BLM)-induced PF, but it is unknown whether the anti-PF of schisandra is related to LOX. In this study, we established models of PF including a mouse model stimulated by BLM and a HFL1 cell model induced by transforming growth factor (TGF)-β1 to evaluate the inhibition effects of Schisandrin C (Sch C) on PF. We observed that Sch C treatment decreased pulmonary indexes compared to control group. Treatment of Sch C showed a significant reduction in the accumulation of ECM as evidenced by decreased expressions of alpha-smooth muscle actin (α-SMA)、fibronectin (FN)、matrix metalloproteinases-2 (MMP2)、MMP9、tissue inhibitor of matrix metalloproteinases (TIMP1) and collagen proteins such as collagen 1A1 (Col 1A1), and Col 3A1. In addition, the expression of LOX in the lung tissue of mice after Sch C treatment was effectively decreased compared with the MOD group. The inhibition effects in vitro were consistent with those in vivo. Mechanistic studies revealed that Sch C significantly inhibited TGF-β1/Smad2/3 and TNF-α/JNK signaling pathways. In conclusion, our data demonstrated that Sch C significantly ameliorated PF in vivo and vitro, which may play an important role by reducing ECM deposition and inhibiting the production of LOX.

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Vardenafil Activity in Lung Fibrosis and In Vitro Synergy with Nintedanib

Cited by 6 publications

References 31 publications

Nintedanib regulates intestinal smooth muscle hyperplasia and phenotype in vitro and in TNBS colitis in vivo

Nintedanib regulates intestinal smooth muscle hyperplasia and phenotype in vitro and in TNBS colitis in vivo

Inhibitory effects of Schisandrin C on collagen behavior in pulmonary fibrosis

Sch C Ameliorates Pulmonary Fibrosis by Inhibiting the Level of LOX

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