miRNA Expression in Fibroblastic Foci within Idiopathic Pulmonary Fibrosis Lungs Reveals Novel Disease-Relevant Pathways

Abstract

miRNAs are 22 nucleotides long and belong to a class of noncoding RNAs that plays an important role in regulating gene expression at a post-transcriptional level. Studies show aberrant levels of miRNAs to be associated with profibrotic processes in idiopathic pulmonary fibrosis (IPF). However, most of these studies used whole IPF tissue or in vitro monocultures in which fibrosis was artificially induced. The current study used laser microdissection to collect fibroblastic foci (FF), the key pathologic lesion in IPF, isolated miRNAs, and compared their expression levels with those found in whole IPF lung tissue and/or in vitro cultured fibroblast from IPF or normal lungs. Sequencing libraries were generated, and data generated were bioinformatically analyzed. A total of 18 miRNAs were significantly overexpressed in FF tissue when compared with whole IPF tissue. Of those, 15 were unique to FF. Comparison of FF with cultured IPF fibroblasts also revealed differences in miRNA composition that impacted several signaling pathways. The miRNA composition of FF is both overlapping and distinct from that of whole IPF tissue or cultured IPF fibroblasts and highlights the importance of characterizing FF biology as a phenotypically and functionally discrete tissue microenvironment. miRNAs are 22 nucleotides long and belong to a class of noncoding RNAs that plays an important role in regulating gene expression at a post-transcriptional level. Studies show aberrant levels of miRNAs to be associated with profibrotic processes in idiopathic pulmonary fibrosis (IPF). However, most of these studies used whole IPF tissue or in vitro monocultures in which fibrosis was artificially induced. The current study used laser microdissection to collect fibroblastic foci (FF), the key pathologic lesion in IPF, isolated miRNAs, and compared their expression levels with those found in whole IPF lung tissue and/or in vitro cultured fibroblast from IPF or normal lungs. Sequencing libraries were generated, and data generated were bioinformatically analyzed. A total of 18 miRNAs were significantly overexpressed in FF tissue when compared with whole IPF tissue. Of those, 15 were unique to FF. Comparison of FF with cultured IPF fibroblasts also revealed differences in miRNA composition that impacted several signaling pathways. The miRNA composition of FF is both overlapping and distinct from that of whole IPF tissue or cultured IPF fibroblasts and highlights the importance of characterizing FF biology as a phenotypically and functionally discrete tissue microenvironment. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by a restrictive ventilatory defect and impaired gas transfer due to deposition of fibrotic tissue in the lung interstitium. The incidence of IPF has been reported as ranging from 2.8 to 18 cases per 100,000.1Hutchinson J. Fogarty A. Hubbard R. McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review.Eur Respir J. 2015; 46: 795-806Crossref PubMed Scopus (543) Google Scholar With 6000 new patients/year presenting and a disease prevalence of approximately 32,000 in the United Kingdom (British Lung Foundation UK IPF Statistics, https://www.blf.org.uk/support-for-you/idiopathic-pulmonary-fibrosis-ipf/statistics, last accessed February 2, 2022), it appears to be increasing steadily. IPF has a poor prognosis, with a median survival of 2 to 4 years from diagnosis, making post-diagnosis survival worse than many cancers.2Ley B. Collard H.R. King T.E. Clinical course and prediction of survival in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2011; 183: 431-440Crossref PubMed Scopus (1170) Google Scholar The etiology of IPF remains unclear, but growing evidence points towards complex interactions between genetic risk factors and environmental insults on a background of age-associated predisposition as the key contributors.3Fingerlin T.E. Murphy E. Zhang W. Peljto A.L. Brown K.K. Steele M.P. et al.Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.Nat Genet. 2013; 45: 613-620Crossref PubMed Scopus (553) Google Scholar, 4Molyneaux P.L. Cox M.J. Willis-Owen S.A.G. Mallia P. Russell K.E. Russell A.M. Murphy E. Johnston S.L. Schwartz D.A. Wells A.U. Cookson W.O.C. Maher T.M. Moffatt M.F. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2014; 190: 906-913Crossref PubMed Scopus (377) Google Scholar, 5Alder J.K. Chen J.J.L. Lancaster L. Danoff S. Su S.C. Cogan J.D. Vulto I. Xie M. Qi X. Tuder R.M. Phillips J.A. Lansdorp P.M. Loyd J.E. Armanios M.Y. Short telomeres are a risk factor for idiopathic pulmonary fibrosis.Proc Natl Acad Sci U S A. 2008; 105: 13051-13056Crossref PubMed Scopus (589) Google Scholar Treatment options for IPF are limited and are predominately palliative. Two distinct pharmaceutical agents, pirfenidone and nintedanib, are licensed as novel IPF treatments. However, at best, these agents decrease the rate of decline in patient lung function and reduce the risk of acute deteriorations of lung function rather than halt or reverse the fibrogenic process.6King T.E. Bradford W.Z. Castro-Bernardini S. Fagan E.A. Glaspole I. Glassberg M.K. Gorina E. Hopkins P.M. Kardatzke D. Lancaster L. Lederer D.J. Nathan S.D. Pereira C.A. Sahn S.A. Sussman R. Swigris J.J. Noble P.W. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (2597) Google Scholar,7Richeldi L. du Bois R.M. Raghu G. Azuma A. Brown K.K. Costabel U. Cottin V. Flaherty K.R. Hansell D.M. Inoue Y. Kim D.S. Kolb M. Nicholson A.G. Noble P.W. Selman M. Taniguchi H. Brun M. Le Maulf F. Girard M. Stowasser S. Schlenker-Herceg R. Disse B. Collard H.R. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (2939) Google Scholar Lung transplantation is the only option that offers hope for long-term survival, but it is only available to highly selected individuals.8Kistler K.D. Nalysnyk L. Rotella P. Esser D. Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature.BMC Pulm Med. 2014; 14: 139Crossref PubMed Scopus (99) Google Scholar The pathology of IPF is characterized by disruption of normal lung architecture due to deposition of excessive collagen and extracellular matrix in the alveolar walls, and of of fibroblasts and which are as fibroblastic foci on of A. P. F. G. M. S. A. J.A. P.M. Hansell D.M. Nicholson A.G. I. Brown K.K. L. of fibroblast foci in idiopathic pulmonary PubMed Google interactions in pulmonary Respir Crit Care Med. PubMed Scopus Google Scholar The foci discrete of lung and and are of importance to the progression of of the that the the FF in the lung to and excessive extracellular matrix is to to new that halt or reverse the disease miRNAs are noncoding RNAs that gene expression in a post-transcriptional to the of their with by the and a miRNA expression levels several and T. Zhang in fibrotic J PubMed Scopus Google Scholar The levels of miRNAs been in several fibrotic in both and disease and been associated with fibrosis H. X. H. H. in idiopathic pulmonary fibrosis: in pathogenesis and in and B. PubMed Scopus Google Scholar However, many of these studies used whole the with the normal studies were on or cultured from or normal tissue or from in which fibrosis has been artificially J. in idiopathic pulmonary 2015; PubMed Scopus Google Scholar of these associated with the of and their in the or from isolated cultured on tissue study on of the role of miRNAs in the of IPF by the expression of miRNAs FF the of IPF that are in fibroblasts and which are to multiple foci from IPF lung tissue were laser microdissection and the miRNA was by The levels of miRNAs in FF were compared with those found in total IPF tissue or in fibroblast isolated from IPF or normal lung tissue to the of on the miRNA these the study novel FF that been of IPF lung tissue from patients were and with The were used for of FF on the FF were and selected by a and and and by of tissue was by and were and used to The study was in with the of in IPF tissue was from patients lung transplantation at the of Foundation The FF were from the IPF tissue The of was an laser were in an and was isolated as per The of was found to to of which at to The foci were from the lung and between RNAs were to the libraries for were from total and a were used to the and of and a were used to the of the and the of the in the libraries was with a and an The libraries were on to the at Lung fibroblasts were isolated from IPF lung tissue that was used for and on fibroblast were by the from normal and were used as The were to for in the the were for with only or with 3 factor The were at and total was the from a on were and with D.M. of data and 2015; PubMed Scopus Google Scholar last accessed was used to the from as miRNA from and miRNA expression D.M. of data and 2015; PubMed Scopus Google Scholar were and for W. S. of and for data with 2014; PubMed Scopus Google and and were for and for and miRNA data be found at the the miRNA of of IPF were from patients were with and and foci were in the of FF IPF to foci were and from lung isolated from foci was on 3 to 4 for The were the and the of miRNAs was The of for miRNA the most miRNA in the FF isolated from whole IPF lung tissue was and a of miRNA in the isolated FF from the lung was a with significantly miRNAs and miRNAs that were significantly overexpressed in the whole IPF lung tissue compared with the foci and 18 miRNAs that are significantly overexpressed in FF compared with the whole IPF lung tissue on a of or and were differences in the levels of their miRNAs were in both with miRNAs unique to IPF lung tissue and 15 miRNAs unique to fibroblastic foci these miRNAs a was revealed miRNAs to IPF and as by their with and as and 2 extracellular and miRNAs in the whole lung were to of multiple as with and the and and long gene long and However, on miRNAs found in isolated fibroblastic foci revealed several found in the on whole IPF tissue that as which are associated with tissue were and also and levels of are associated with lung function in J. R. T. Y. S. T. Y. A. S. Y. association with and lung disease in PubMed Scopus Google Scholar and Y. Y. Chen S. Y. D. J. S. Chen H. as of disease and in patients with idiopathic pulmonary PubMed Scopus Google Scholar is reported to to regulating P. Chen P. A. M. a in the and in to and PubMed Scopus Google Scholar as long and several miRNAs and were also to be associated to miRNAs from isolated FF but were found in on whole lung IPF in of are in in IPF, idiopathic pulmonary transfer total lung transfer in a new expression of miRNAs in idiopathic pulmonary fibrosis (IPF) and fibroblastic foci isolated from the of the miRNAs in the between fibroblastic foci isolated from IPF and whole IPF lung tissue and from to to of the significantly overexpressed miRNAs in fibroblastic foci are in overexpressed miRNAs in whole IPF lung are in and of the miRNAs with in at per unique miRNAs in fibroblastic unique miRNAs in whole IPF and overlapping miRNAs found in in both FF and whole IPF tissue. laser expression of miRNAs in idiopathic pulmonary fibrosis (IPF) and fibroblastic foci isolated from the of miRNAs found in whole IPF lung tissue and fibroblastic foci and overexpressed miRNAs are in and of and is in and to miRNAs for which prediction of be are in between the and miRNAs, as in the of are in in IPF, idiopathic pulmonary transfer total lung transfer these data show that the of of whole the and expression of miRNAs from a highly of the it was to the miRNA expression FF by the miRNA of in vitro fibroblasts isolated from IPF that FF was fibroblasts were isolated from the IPF used for of FF by and the miRNA of in vitro were compared with generated FF Of the most miRNA in the miRNAs in FF and unique miRNAs in cultured fibroblasts data were used to the of and by the miRNAs a of of and by miRNAs were found in both FF and fibroblasts by miRNAs were unique to FF and an of and to miRNAs were in IPF fibroblasts in vitro of the most miRNAs in several signaling unique to FF be to the data to the biology of cultured IPF fibroblasts with to in the FF tissue of the of and miRNAs in fibroblastic foci and cultured fibroblasts isolated from idiopathic pulmonary fibrosis (IPF) A and of miRNAs with expression in fibroblastic foci and cultured IPF and overexpressed miRNAs are in and of and is in and to miRNAs for which prediction of be are in between the and miRNAs, as in the gene by in vitro isolated lung fibroblasts are a in the of in vitro fibroblasts cultured on miRNA expression that the and of the were isolated from was fibroblasts from IPF and/or normal were isolated and and the expression of miRNAs the in vitro were compared miRNAs were significantly overexpressed in the normal lung fibroblasts and and 15 miRNAs were significantly overexpressed in IPF fibroblasts and data also show a in the and between the IPF and normal lung that the of in vitro the that tissue of is at when miRNAs with in at per miRNAs were found to be miRNAs were only in normal and were unique to IPF revealed that miRNAs in fibroblasts from IPF were found to be to the factor factor 4 and the factor 2 miRNAs and 4 and factor and 4 and and collagen the of IPF and normal lung the were with to the to miRNAs were isolated and The miRNAs that were significantly overexpressed in the IPF fibroblasts with and and 3 miRNAs that were significantly compared with the fibroblasts from normal with and revealed that 3 of significantly overexpressed miRNAs in the IPF lung fibroblasts are due to with with the miRNAs as between the IPF and normal lung fibroblasts the overexpressed miRNAs in normal lung fibroblasts were at Of the miRNAs in cultured lung were to normal and IPF were unique to normal fibroblasts and were unique to the IPF cultured fibroblasts these miRNAs to be associated with several of which were also found to miRNAs in fibroblasts from IPF the miRNAs and and the and the with was also the factor several 2, 2 and the factor and with and data that the in vitro of fibroblasts is a that the with a of fibrogenic has data show that on miRNA expression levels in fibroblasts that of be or expression of miRNAs in fibroblasts isolated from normal and idiopathic pulmonary fibrosis (IPF) of the miRNAs with in at per unique miRNAs in IPF unique miRNAs in fibroblasts from normal and overlapping miRNAs found in in both fibroblasts isolated from normal and IPF lungs. of miRNAs in fibroblasts isolated from normal and IPF lungs. and overexpressed miRNAs are in and of and is in and to miRNAs for which prediction of be are in between the and miRNAs, as in the expression of miRNAs in fibroblasts isolated from normal and idiopathic pulmonary fibrosis (IPF) with factor of the miRNAs in the between IPF lung and normal lung cultured fibroblasts both with and of the miRNAs IPF lung and normal lung cultured fibroblasts with significantly overexpressed miRNAs in normal lung fibroblasts with are in significantly overexpressed miRNAs in IPF fibroblasts with are in miRNAs that as a of with are in expression of miRNAs in fibroblasts isolated from normal and idiopathic pulmonary fibrosis (IPF) with factor of the miRNAs with in at per unique miRNAs in IPF fibroblasts with unique miRNAs in fibroblasts from normal and overlapping miRNAs found in in of miRNAs in fibroblasts isolated from normal and IPF both with and overexpressed miRNAs are in and of and is in and to miRNAs for which prediction of be are in between the and miRNAs, as in the miRNAs are noncoding that function in post-transcriptional of gene with miRNAs gene expression in and study the role of miRNAs in the of IPF by their expression fibroblastic the IPF highly in extracellular as fibroblasts and of these are of importance in of the novel of disease fibroblastic foci were isolated from IPF laser generated a of that were in of the miRNA by those to the disease these it was to novel signaling and by miRNAs the current data show that it is to from the isolated fibroblasts or whole IPF lung tissue. these and in of the studies several miRNAs found in IPF tissue or IPF with these the of and and the of most of these miRNAs was and in IPF fibroblastic and IPF cultured fibroblasts were is that miRNAs, are studies used whole IPF lung tissue or isolated and cultured lung fibroblasts to miRNA foci the IPF lung which are the to IPF a of lung found in a whole be used to processes that progression of IPF, that those processes are to be by from the was study several important novel and be by that are unique to FF in IPF is it to the miRNA expression FF by growing in and their miRNA fibroblasts cultured on miRNA expression that the and of the were isolated or lung fibroblasts on in miRNA only miRNAs were found to be significantly in FF and IPF and Of and been in H. X. H. H. in idiopathic pulmonary fibrosis: in pathogenesis and in and B. PubMed Scopus Google A. R. of expression in a for lung PubMed Scopus Google Scholar, S. H. Xie M. S. E. G. and lung J. 2013; PubMed Scopus Google Scholar, S.L. T. G. to associated with in lung J Google Scholar However, to and been to be to studies as a key of and in a of S. of and in tissue to and PubMed Scopus Google Scholar, A. H. and to and and decrease the of PubMed Scopus Google Scholar, M. Zhang X. X. Y. H. H. H. P. X. Y. noncoding progression by in and Scopus Google Scholar, Y. Y. J. X. L. J. progression of PubMed Scopus Google Scholar in lung has been to in patients with lung G. P. S. in lung by regulating PubMed Scopus Google W. B. J. of the of lung to by and regulating the of Google Scholar The of Zhang et W. B. J. of the of lung to by and regulating the of Google Scholar that the of the to of lung the of the 2 and S. of plays a role in in 2014; PubMed Scopus Google Scholar as of in cultured the has been associated with pulmonary of in the pathogenesis of pulmonary PubMed Scopus Google Scholar, P. J. I. J. of in lung and J PubMed Scopus Google Scholar, J. T. Xie J. L. Chen R. P. J. lung fibrosis in and J Med. 2014; Google Scholar The current show and to be in both FF and IPF of was in the of patients with with lung when compared with patients with lung disease of the that to in patients with with lung D. D. J. X. and novel for lung disease with PubMed Scopus Google Scholar However, in IPF has been of miRNAs were found to be only in but in IPF, with or these miRNAs, been in IPF H. X. H. H. in idiopathic pulmonary fibrosis: in pathogenesis and in and B. PubMed Scopus Google A. R. of expression in a for lung PubMed Scopus Google Scholar, S. H. Xie M. S. E. G. and lung J. 2013; PubMed Scopus Google Scholar, S.L. T. G. to associated with in lung J Google G. M. F. D. I. miRNA from and lung tissue of and IPF J PubMed Scopus Google Scholar, J.E. F. S. M. G. A. F. X. J. Zhang J. J. L. R. A. D. of fibrosis progression in the PubMed Scopus Google Scholar, L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google Scholar, L. A. M. I. A.L. Flaherty K.R. D. A defect in idiopathic pulmonary 2011; PubMed Scopus Google Scholar, T. M. H. Y. the of and the progression of PubMed Scopus Google Scholar, X. J. G. Y. S. the of by of signaling in a pulmonary fibrosis PubMed Scopus Google Scholar, J. to pulmonary fibrosis by regulating J Med. PubMed Scopus Google Scholar, Zhang Zhang M.Y. Chen of an in whole for of and PubMed Scopus Google Scholar, H. A. A. T. in and in idiopathic pulmonary fibrosis and their PubMed Scopus Google Scholar, Y. H. J. D. F. Y. L. Chen X. X. J. of signaling of fibrosis PubMed Scopus Google Scholar, P. J. Chen T. H. H. J. W. Y. Y. Y. G. Zhang G. of in idiopathic pulmonary J Med. 2014; PubMed Scopus Google Scholar, T. J. R. Noble P.W. D. in pulmonary fibrosis identifies multiple of 2011; PubMed Scopus Google Scholar, H. S. Xie J. R.M. S. G. is a of lung fibrosis by J Respir PubMed Scopus Google Scholar, S. Kim G. K.D. J.A. A. J. D.J. Collard H.R. in alveolar of patients with idiopathic pulmonary PubMed Scopus Google Scholar, S. H. Y. Zhang J. H. W. G. P. Zhang J. X. by of in idiopathic pulmonary J PubMed Scopus Google Scholar, B. T. X. L. H. L. of in from idiopathic pulmonary fibrosis Google Scholar, T. E. P. L. M. A novel miRNA identifies as a for fibrosis in patients with Scopus Google Scholar, H. Zhang Y. Chen Y. T. X. Y. L. Y. Zhang B. S. Y. H. The and of in idiopathic pulmonary 2014; PubMed Scopus Google Scholar, Y. S. the from fibrosis to in patients with Med. Google Scholar, A. S. Raghu G. factors and to and fibrotic PubMed Scopus Google Scholar, X. Y. A. Y. X. X. D. C.A. L. pulmonary fibrosis by fibroblast and PubMed Scopus Google Scholar, S. S. A. S. E. G. of in pulmonary fibrosis.Am J PubMed Scopus Google Scholar, S. F. B. L. M. S. M. S. M. reduce and idiopathic pulmonary fibrosis alveolar PubMed Scopus Google Scholar, S. M. Y. M. S. X. L. Y. the and fibrosis in disease by PubMed Scopus Google Scholar, B. Kolb M. P. M. expression in pulmonary J 2014; PubMed Scopus Google Scholar, D. H. M. A. S.A. M. D. T. Selman M. S.C. A. A. D. P. and role of in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. PubMed Scopus Google Scholar, E. S. B. F. E. J. J. J. B. P. T. M. B. is fibrogenic to tissue and lung fibroblast by Genet. 2013; PubMed Scopus Google to the of been as to several miRNAs been in fibrotic disease in and been in and and been to and fibrosis Of and to IPF or and their expression in it be to these miRNAs for novel in these that the of whole or in vitro fibroblast the from IPF with IPF Lung in G. M. F. D. I. miRNA from and lung tissue of and IPF J PubMed Scopus Google J.E. F. S. M. G. A. F. X. J. Zhang J. J. L. R. A. D. of fibrosis progression in the PubMed Scopus Google L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google J.E. F. S. M. G. A. F. X. J. Zhang J. J. L. R. A. D. of fibrosis progression in the PubMed Scopus Google L. A. M. I. A.L. Flaherty K.R. D. A defect in idiopathic pulmonary 2011; PubMed Scopus Google L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google T. M. H. Y. the of and the progression of PubMed Scopus Google X. J. G. Y. S. the of by of signaling in a pulmonary fibrosis PubMed Scopus Google L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google J. to pulmonary fibrosis by regulating J Med. PubMed Scopus Google and L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google Zhang Zhang M.Y. Chen of an in whole for of and PubMed Scopus Google L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google H. A. A. T. in and in idiopathic pulmonary fibrosis and their PubMed Scopus Google L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google Y. H. J. D. F. Y. L. Chen X. X. J. of signaling of fibrosis PubMed Scopus Google in A. R. of expression in a for lung PubMed Scopus Google J.E. F. S. M. G. A. F. X. J. Zhang J. J. L. R. A. D. of fibrosis progression in the PubMed Scopus Google J.E. F. S. M. G. A. F. X. J. Zhang J. J. L. R. A. D. of fibrosis progression in the PubMed Scopus Google H. X. H. H. in idiopathic pulmonary fibrosis: in pathogenesis and in and B. PubMed Scopus Google A. R. of expression in a for lung PubMed Scopus Google L. L. F. T. J. G. D.A. J. in the of that are between and PubMed Scopus Google H. A. A. T. in and in idiopathic pulmonary fibrosis and their PubMed Scopus Google P. J. Chen T. H. H. J. W. Y. Y. Y. G. Zhang G. of in idiopathic pulmonary J Med. 2014; PubMed Scopus Google T. J. R. Noble P.W. D. in pulmonary fibrosis identifies multiple of 2011; PubMed Scopus Google H. X. H. H. in idiopathic pulmonary fibrosis: in pathogenesis and in and B. PubMed Scopus Google A. R. of expression in a for lung PubMed Scopus Google H. S. Xie J. R.M. S. G. is a of lung fibrosis by J Respir PubMed Scopus Google A. R. of expression in a for lung PubMed Scopus Google J.E. F. S. M. G. A. F. X. J. Zhang J. J. L. R. A. D. of fibrosis progression in the PubMed Scopus Google S. Kim G. K.D. J.A. A. J. D.J. Collard H.R. in alveolar of patients with idiopathic pulmonary PubMed Scopus Google A. R. of expression in a for lung PubMed Scopus Google J.E. F. S. M. G. A. F. X. J. Zhang J. J. L. R. A. D. of fibrosis progression in the PubMed Scopus Google S. H. Y. Zhang J. H. W. G. P. Zhang J. X. by of in idiopathic pulmonary J PubMed Scopus Google B. T. X. L. H. L. of in from idiopathic pulmonary fibrosis Google A. R. of expression in a for lung PubMed Scopus Google T. E. P. L. M. A novel miRNA identifies as a for fibrosis in patients with Scopus Google H. X. H. H. in idiopathic pulmonary fibrosis: in pathogenesis and in and B. PubMed Scopus Google A. R. of expression in a for lung PubMed Scopus Google J.E. F. S. M. G. A. F. X. J. Zhang J. J. L. R. A. D. of fibrosis progression in the PubMed Scopus Google H. Zhang Y.

Topics & Concepts