Type I Collagen-Targeted PET Imaging in Idiopathic Pulmonary Fibrosis: First-in-Human Studies

2019 ◽  
Author(s):  
S.B. Montesi ◽  
D. Izquierdo-Garcia ◽  
E.D. Abston ◽  
P. Desogere ◽  
S. Digumarthy ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Pet Imaging ◽  
Type I Collagen ◽  
Human Studies ◽  
Type I

scholarly journals Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis

2008 ◽  
Vol 205 (7) ◽  
pp. 1659-1672 ◽  
Author(s):  
Hong Xia ◽  
Deanna Diebold ◽  
Richard Nho ◽  
David Perlman ◽  
Jill Kleidon ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Type I Collagen ◽  
Tissue Injury ◽  
Signal Pathway ◽  
Lung Fibroblasts ◽  
Integrin Signaling ◽  
Type I ◽  
Β1 Integrin ◽  
Fibroblast Proliferation

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease in which fibroblasts accumulate in the alveolar wall within a type I collagen–rich matrix. Although lung fibroblasts derived from patients with IPF display durable pathological alterations in proliferative function, the molecular mechanisms differentiating IPF fibroblasts from their normal counterparts remain unknown. Polymerized type I collagen normally inhibits fibroblast proliferation, providing a physiological mechanism to limit fibroproliferation after tissue injury. We demonstrate that β1 integrin interaction with polymerized collagen inhibits normal fibroblast proliferation by suppression of the phosphoinositide 3-kinase (PI3K)–Akt–S6K1 signal pathway due to maintenance of high phosphatase activity of the tumor suppressor phosphatase and tensin homologue (PTEN). In contrast, IPF fibroblasts eluded this restraint, displaying a pathological pattern of β1 integrin signaling in response to polymerized collagen that leads to aberrant activation of the PI3K–Akt–S6K1 signal pathway caused by inappropriately low PTEN activity. Mice deficient in PTEN showed a prolonged fibroproliferative response after tissue injury, and immunohistochemical analysis of IPF lung tissue demonstrates activation of Akt in cells within fibrotic foci. These results provide direct evidence for defective negative regulation of the proliferative pathway in IPF fibroblasts and support the theory that the pathogenesis of IPF involves an intrinsic fibroblast defect.

scholarly journals Reduced FoxO3a expression causes low autophagy in idiopathic pulmonary fibrosis fibroblasts on collagen matrices

2015 ◽  
Vol 309 (6) ◽  
pp. L552-L561 ◽  
Author(s):  
Jintaek Im ◽  
Polla Hergert ◽  
Richard Seonghun Nho
Keyword(s):  
Cell Death ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Type I Collagen ◽  
Collagen Matrix ◽  
Dominant Negative ◽  
Luciferase Assay ◽  
Type I ◽  
Protein Levels ◽  
Autophagic Activity

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease, and fibroblasts derived from patients with IPF are resistant to type I collagen matrix-induced cell death. The alteration of the PTEN-Akt axis permits IPF fibroblasts to maintain a pathological phenotype on collagen by suppressing autophagy. However, the precise underlying mechanism by which the Akt downstream molecule suppresses autophagic activity remains elusive. FoxO3a is a direct target of Akt and is implicated with the transcriptional activation of autophagy. Therefore, we investigated whether reduced FoxO3a expression causes abnormally low autophagy in IPF fibroblasts on collagen. We found that FoxO3a mRNA and protein levels are low in IPF fibroblasts, which subsequently suppresses the autophagosomal marker LC3B expression on collagen matrix. In contrast, the majority of control fibroblasts showed an increase in FoxO3a and LC3B expression at both the mRNA and protein levels. The luciferase assay confirmed that FoxO3a binds to the promoter region of LC3B and transcriptionally activates LC3B. The overexpression of wild-type FoxO3a increased LC3B mRNA and protein expression in IPF fibroblasts, whereas the dominant negative FoxO3a decreased the LC3B level in control fibroblasts. The inhibition of autophagic activity sensitized control fibroblasts to collagen matrix-induced cell death. In contrast, enhanced viability was found when autophagic function was inhibited in IPF fibroblasts. Our study showed that aberrantly low FoxO3a expression participates in reducing autophagic activity via transcriptional suppression of LC3B in IPF fibroblasts on collagen. This suggests that low autophagic activity by the alteration of FoxO3a may contribute to IPF progression.

scholarly journals Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
H. Jessen ◽  
N. Hoyer ◽  
T. S. Prior ◽  
P. Frederiksen ◽  
M. A. Karsdal ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Disease Progression ◽  
Real World ◽  
Progressive Disease ◽  
Type Iii Collagen ◽  
Type I ◽  
Collagen Turnover ◽  
Baseline Levels ◽  
Longitudinal Biomarker

Abstract Background Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of fibrillar collagens in the alveolar space resulting in reduced pulmonary function and a high mortality rate. Biomarkers measuring the turnover of type I and III collagen could provide valuable information for prognosis and treatment decisions in IPF. Methods Serological biomarkers reflecting the formation of type III collagen (PRO-C3) and degradation of type I (C1M) and III collagen (C3M) were evaluated in a real-world cohort of 178 newly diagnosed IPF patients. Blood samples and clinical data were collected at baseline, six, and 12 months. Baseline and longitudinal biomarker levels were related to disease progression of IPF (defined as ≥ 5% decline in forced vital capacity (FVC) and/or ≥ 10% decline in diffusing capacity for carbon monoxide (DLco) and/or all-cause mortality at 12 months). Furthermore, we analysed differences in percentage change of biomarker levels from baseline between patients receiving antifibrotic treatment or not. Results Increased baseline levels of type I and III collagen turnover biomarkers were associated with a greater risk of disease progression within 12 months compared to patients with a low baseline type I and III collagen turnover. Patients with progressive disease had higher serum levels of C1M (P = 0.038) and PRO-C3 (P = 0.0022) compared to those with stable disease over one year. There were no differences in biomarker levels between patients receiving pirfenidone, nintedanib, or no antifibrotics. Conclusion Baseline levels of type I and III collagen turnover were associated with disease progression within 12 months in a real-world cohort of IPF patients. Longitudinal biomarker levels of type I and III collagen turnover were related to progressive disease. Moreover, antifibrotic therapy did not affect type I and III collagen turnover biomarkers in these patients. PRO-C3 and C1M may be potential biomarkers for a progressive disease behavior in IPF.

scholarly journals Antioxidant Activity Mediates Pirfenidone Antifibrotic Effects in Human Pulmonary Vascular Smooth Muscle Cells Exposed to Sera of Idiopathic Pulmonary Fibrosis Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Alessandro Giuseppe Fois ◽  
Anna Maria Posadino ◽  
Roberta Giordo ◽  
Annalisa Cossu ◽  
Abdelali Agouni ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Smooth Muscle Cells ◽  
Antioxidant Properties ◽  
Muscle Cells ◽  
Pulmonary Vasculature ◽  
Ros Generation ◽  
Type I ◽  
Causative Role

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by an exacerbated fibrotic response. Although molecular and cellular determinants involved in the onset and progression of this devastating disease are largely unknown, an aberrant remodeling of the pulmonary vasculature appears to have implications in IPF pathogenesis. Here, we demonstrated for the first time that an increase of reactive oxygen species (ROS) generation induced by sera from IPF patients drives both collagen type I deposition and proliferation of primary human pulmonary artery smooth muscle cells (HPASMCs). IPF sera-induced cellular effects were significantly blunted in cells exposed to the NADPH oxidase inhibitor diphenyleneiodonium (DPI) proving the causative role of ROS and suggesting their potential cellular source. Contrary to IPF naive patients, sera from Pirfenidone-treated IPF patients failed to significantly induce both ROS generation and collagen synthesis in HPASMCs, mechanistically implicating antioxidant properties as the basis for the in vivo effect of this drug.

scholarly journals Protective Effect of Type I Collagen Antisense Oligonucleotides on Bleomycin Induced Pulmonary Fibrosis

2010 ◽  
Vol 1 (1) ◽  
pp. 141-149 ◽  
Author(s):  
Rahul K.Nath ◽  
Chandra Somasundaram ◽  
Weijun Xiong ◽  
Jessica Li ◽  
Ka Bian ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Protective Effect ◽  
Antisense Oligonucleotides ◽  
Type I Collagen ◽  
Type I
Sign in / Sign up

Export Citation Format

Share Document