New Insights into the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis

Ding, Qiang; Luckhardt, Tracy; Hecker, Louise; Zhou, Yong; Liu, Gang; Antony, Veena B.; deAndrade, Joao; Thannickal, Victor J.

doi:10.2165/11591490-000000000-00000

Cited by 59 publications

(47 citation statements)

References 180 publications

(241 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is well recognized that multiple cell types and pathways play important roles in the development of IPF (19). The altered ECM and immune microenvironment surrounding the invading myofibroblasts and other cell types contribute to the anatomic and physiological changes representing the lung the IPF (20,21).…”

Section: Discussionmentioning

confidence: 99%

3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs

Surolia¹,

Li²,

Wang³

et al. 2017

JCI Insight

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs

Surolia¹,

Li²,

Wang³

et al. 2017

JCI Insight

Self Cite

View full text Add to dashboard Cite

“…This disappearance may involve dedifferentiation of myofibroblasts to the quiescent progenitor phenotype (7) or clearance of apoptotic or senescent myofibroblasts (8)(9)(10). In contrast, the persistence of myofibroblasts in injured tissues leads to nonresolving and progressive fibrosis, as exemplified by human idiopathic pulmonary fibrosis (IPF) (11).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis

et al. 2013

Self Cite

View full text Add to dashboard Cite

Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 (MKL1), that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic pulmonary fibrosis (IPF), we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.

show abstract

“…This disease is characterized by focal areas of alveolar epithelial cell injury and the excessive proliferation of mesenchymal cells in the interstitium, which results in the excessive deposition of extracellular matrix (ECM) and distorted architecture leading to impaired gas exchange (2,3). Although many pathobiological concepts are emerging, including the role of aging and cellular senescence, oxidative stress, endoplasmic reticulum stress, cellular plasticity, microRNA (miRNA) and mechanotransduction, the molecular mechanisms behind IPF are not yet completely understood (4).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of long non-coding RNAs in bleomycin-induced lung fibrosis

Cao

Zhang

Wang

et al. 2013

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Abstract. Recent studies suggest that long non-coding RNAs (lncRNAs) are more involved in human diseases than previously realized. A growing body of evidence links lncRNA mutation and dysregulation to diverse human diseases. However, the association of lncRNAs with the pathogenesis of lung fibrosis remains poorly understood. In this study, we detected changes in hydroxyproline and collagen levels, as well as the ultrastructure of lung tissue to develop a rat model of lung fibrosis. The differentially expressed lncRNAs and mRNA profiles between fibrotic lung and normal lung tissue were analyzed using microarrays. Gene Ontology analysis and pathway analysis were performed for further research. Two differentially expressed lncRNAs, namely, AJ005396 and S69206, were detected by in situ hybridization to validate the microarray data. The results revealed that the number of collagen fibers in the interstitial lung tissue significantly increased in the model group compared with the normal group. In total, 210 and 358 lncRNAs were upregulated and downregulated, respectively, along with 415 upregulated and 530 downregulated mRNAs in the rats with lung fibrosis. AJ005396 and S69206 were upregulated in the fibrotic lung tissue, consistent with the microarray data, and were located in the cytoplasm of the interstitial lung cells. In conclusion, the expression profile of the lncRNAs was significantly altered in the fibrotic lung tissue and these transcripts are potential molecular targets for inhibiting the development of lung fibrosis. IntroductionIdiopathic pulmonary fibrosis (IPF) is a common, chronic, progressive and usually lethal fibrotic lung disease with poor prognosis (1). This disease is characterized by focal areas of alveolar epithelial cell injury and the excessive proliferation of mesenchymal cells in the interstitium, which results in the excessive deposition of extracellular matrix (ECM) and distorted architecture leading to impaired gas exchange (2,3). Although many pathobiological concepts are emerging, including the role of aging and cellular senescence, oxidative stress, endoplasmic reticulum stress, cellular plasticity, microRNA (miRNA) and mechanotransduction, the molecular mechanisms behind IPF are not yet completely understood (4).The Encyclopedia of DNA Elements (ENCODE) project, which aimed to comprehensively characterize the human genome, has shown that >90% of the genome has been transcribed; however, only 1-2% of that is composed of genes (5). The majority of these transcripts are not translated into proteins and are, therefore, termed non-coding RNAs (ncRNAs).Long non-coding RNAs (lncRNAs), a type of ncRNA, vary in size from 200 bp to >100 kb, and are transcribed by RNA polymerase II (6). They play an important role in imprinting (7), enhancing various biological functions (8), X chromosome inactivation (9), chromatin structure (10) and genomic rearrangement during the generation of antibody diversity (11). Thus, lncRNAs are critical for normal development and, in many cases, are deregulated in d...

show abstract

New Insights into the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis

Cited by 59 publications

References 180 publications

3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs

3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs

Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis

Differential expression of long non-coding RNAs in bleomycin-induced lung fibrosis

Contact Info

Product

Resources

About