Emphysematous Lesions, Inflammation, and Fibrosis in the Lungs of Transgenic Mice Overexpressing Platelet-Derived Growth Factor

Because of its expression pattern and its potent effects on mesenchymal cells, platelet-derived growth factor (PDGF) has been implicated as an important factor in epithelial-mesenchymal cell interactions during normal lung development and in the pathogenesis of fibrotic lung disease. To further explore the role of PDGF in these processes, we have developed transgenic mice that express the PDGF-B gene from the lung-specific surfactant protein C (SPC) promoter. Adult SPC-PDGFB transgenic mice exhibited lung pathology characterized by enlarged airspaces, inflammation, and fibrosis. Emphysematous changes frequently occurred throughout the lung, but inflammation and fibrotic lesions were usually confined to focal areas. The severity of this phenotype varied significantly among individual mice within the same SPC-PDGFB transgenic lineage. A pathology similar to that observed in adult mice was noted in lungs from transgenic mice as young as 1 week of age. Neonatal transgenic mice exhibited enlarged saccules and thickened primary septa. Results of these studies indicated that overexpression of PDGF-B induced distinct abnormalities in the developing and adult lung and led to a complex phenotype that encompassed aspects of both emphysema and fibrotic lung disease. Because of its expression pattern and its potent effects on mesenchymal cells, platelet-derived growth factor (PDGF) has been implicated as an important factor in epithelial-mesenchymal cell interactions during normal lung development and in the pathogenesis of fibrotic lung disease. To further explore the role of PDGF in these processes, we have developed transgenic mice that express the PDGF-B gene from the lung-specific surfactant protein C (SPC) promoter. Adult SPC-PDGFB transgenic mice exhibited lung pathology characterized by enlarged airspaces, inflammation, and fibrosis. Emphysematous changes frequently occurred throughout the lung, but inflammation and fibrotic lesions were usually confined to focal areas. The severity of this phenotype varied significantly among individual mice within the same SPC-PDGFB transgenic lineage. A pathology similar to that observed in adult mice was noted in lungs from transgenic mice as young as 1 week of age. Neonatal transgenic mice exhibited enlarged saccules and thickened primary septa. Results of these studies indicated that overexpression of PDGF-B induced distinct abnormalities in the developing and adult lung and led to a complex phenotype that encompassed aspects of both emphysema and fibrotic lung disease. Platelet-derived growth factor (PDGF) is a polypeptide growth factor that has pleiotropic effects on a number of cell types, particularly those of mesenchymal origin. PDGF was originally characterized as the predominant mitogen in serum.1Ross R Glomset JA Kariya B Harker L A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cell in vitro.Proc Natl Acad Sci USA. 1974; 71: 1207-1210Crossref PubMed Scopus (1338) Google Scholar Serum-derived PDGF originates in megakaryocytes and is stored in the α granules of platelets. PDGF was subsequently found to be produced by a variety of cell types, including macrophages and epithelial, endothelial, mesenchymal, and neuronal cells.2Ross R Raines EW Bowen-Pope DF The biology of platelet-derived growth factor.Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1665) Google Scholar PDGF has been demonstrated to be essential for normal development3Bostrom H Willetts K Pekny M Leveen P Lindahl P Hedstrand H Pekna M Hellstrom M Gebre-Medhin S Schalling M Nilsson M Kurland S Tornell J Heath JK Betsholtz C PDGF-A signaling is a critical event in lung alveolar myofibroblast development.Cell. 1996; 85: 863-873Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar, 4Leveen P Pekny M Gebre-Medhin S Swolin B Larsson E Betsholtz C Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities.Genes Dev. 1994; 8: 1875-1887Crossref PubMed Scopus (896) Google Scholar and has been implicated in disease processes such as atherosclerosis and lung fibrosis.5Antoniades HN Bravo MA Avila RE Galanopoulos T Neville-Golden J Selman M Platelet-derived growth factor in idiopathic pulmonary fibrosis.J Clin Invest. 1990; 86: 1055-1064Crossref PubMed Scopus (323) Google Scholar, 6Ross R Masuda J Raines EW Gown AM Katsuda S Sasahara M Malden LT Masuko H Sato H Localization of PDGF-B protein in macrophages in all phases of atherogenesis.Science. 1990; 248: 1009-1012Crossref PubMed Scopus (492) Google Scholar Active PDGF consists of two homologous subunits, A and B, which can form three dimeric PDGF isoforms (AA, AB, and BB).7Hammacher A Hellman U Johnsson A Ostman A Gunnarsson K Westermark B Wasteson A Heldin C-H A major part of platelet-derived growth factor purified from human platelets is a heterodimer of one A and one B chain.J Biol Chem. 1988; 263: 16493-16498Abstract Full Text PDF PubMed Google Scholar, 8Hammacher A Nister M Westermark B Heldin C-H A human glioma cell line secretes three structurally and functionally different dimeric forms of platelet-derived growth factor.Eur J Biochem. 1988; 176: 179-186Crossref PubMed Scopus (60) Google Scholar, 9Heldin C-H Johnsson A Wennergren S Wernstedt C Betsholtz C Westermark B A human osteosarcoma cell line secrets a growth factor structurally related to a homodimer of PDGF-A chains.Nature. 1986; 319: 511-514Crossref PubMed Scopus (291) Google Scholar PDGF dimers bind to specific receptors that themselves are dimers formed from two types of subunits, α and β, that differentially bind PDGF isoforms.10Seifert R Bowen-Pope DF different to platelet-derived growth factor Biol Chem. Full Text PDF PubMed Google Scholar, R Bowen-Pope DF of PDGF different isoforms of 1988; PubMed Scopus Google Scholar The the and and the all three types of PDGF PDGF receptors are found on mesenchymal EW Bowen-Pope DF R Platelet-derived growth and Google Scholar PDGF is produced in adult in but its expression are for EW Bowen-Pope DF R Platelet-derived growth and Google Scholar PDGF is in normal adult lung but is in human lung disease and in of lung of lung Scholar from idiopathic pulmonary of PDGF and of PDGF to macrophages from normal of platelet-derived growth and gene expression in alveolar macrophages of idiopathic pulmonary fibrosis.J Clin Invest. 1990; 85: PubMed Scopus Google Scholar, of platelet-derived growth factor by alveolar macrophages from idiopathic pulmonary J PubMed Scopus Google Scholar of PDGF-B and have been found in and macrophages of idiopathic pulmonary fibrosis.5Antoniades HN Bravo MA Avila RE Galanopoulos T Neville-Golden J Selman M Platelet-derived growth factor in idiopathic pulmonary fibrosis.J Clin Invest. 1990; 86: 1055-1064Crossref PubMed Scopus (323) Google Scholar PDGF-B was in and macrophages in lung from idiopathic pulmonary but PDGF-B was in M M M of platelet-derived growth factor in normal and fibrotic lung is both macrophages and alveolar express the J PubMed Scopus Google Scholar have been in from a characterized by pulmonary M J of pulmonary Platelet-derived growth factor in the Clin 1994; Google Scholar an of pulmonary induced of PDGF-A and in and macrophages of JA of PDGF-A and expression of lung in J PubMed Scopus Google Scholar Because of its effects on mesenchymal cell proliferation and and its expression in human lung disease and of lung PDGF is to an important role in lung and growth are during the development of lung disease. To fibrotic lung disease can be by PDGF we transgenic mice that express the PDGF-B gene from the lung-specific surfactant protein C (SPC) promoter. we that SPC-PDGFB transgenic mice lung disease characterized by enlarged airspaces, which in were throughout the lung, as as inflammation and which were focal in that PDGF has potent effects on lung growth and development and that its expression can lung pathology characterized by of two distinct emphysema and lung fibrosis. The SPC-PDGFB from the human from the and from the human PDGF-B To human were on the human JA human pulmonary surfactant Biol Chem. 1988; 263: Full Text PDF PubMed Google Scholar and to a from the of the gene by The was as a to a human in the and that to the were The that lung-specific expression in transgenic JA from human surfactant protein gene cell in transgenic J Google Scholar, JA from the human gene expression in the of transgenic PubMed Scopus Google Scholar was and a for further The of this was by and from the gene was in the SPC-PDGFB from the PDGF-B to to the and the the and and a of the can expression of in Natl Acad Sci USA. PubMed Scopus Google Scholar The PDGF-B was from The PDGF-B was from and and of the and PDGF-B from to the to the and A and the PDGF-B L B T of the of the human of the and of expression of the protein by PubMed Scopus Google Scholar mice were by of the SPC-PDGFB as the of mice by Natl Acad Sci USA. PubMed Scopus Google Scholar SPC-PDGFB transgenic mice were by of a from human mice were on a of the and and transgenic were by transgenic to Mice were specific in of for the and of of has been found in SPC-PDGFB mice mice from the in which the transgenic mice were have observed inflammation in the lungs of mice in mice to was by of R RE JA K in Scholar was to JA B M of the lung in J PubMed Scopus Google Scholar a from the human PDGF-B gene that both human and PDGF-B were subsequently a human the protein as a J as an is the for human PubMed Scopus Google Scholar, JA and of in and PubMed Scopus Google Scholar PDGF was in lung a that isoforms the PDGF-B for platelet-derived growth to the of C M and Scholar, A proliferation of lung induced by the platelet-derived growth and isoforms by alveolar J PubMed Scopus Google Scholar were and the and in 1 of 1 and were and and for PDGF was in of by PDGF in lung were to protein as by serum as a lungs were by of for by by were in and was by the of but was and of and Scholar, Scholar were in by the of of of the of Scholar was by an similar to that M expression of growth in the of J 1996; Google Scholar lung were a a from the PDGF-B R Masuda J Raines EW Gown AM Katsuda S Sasahara M Malden LT Masuko H Sato H Localization of PDGF-B protein in macrophages in all phases of atherogenesis.Science. 1990; 248: 1009-1012Crossref PubMed Scopus (492) Google Scholar, T S K K T T of human platelet-derived growth factor a of its PubMed Scopus Google Scholar a of was by of the and were by an was of the of the one from of was to the of lung that exhibited were S in Google Scholar by the of by were on from an were on from an a the and from the were and the of the that was was were in from transgenic and was to the of the the two of A which we have was as an of the of the septa. is to the by B C MA in the 1994; PubMed Scopus Google Scholar and is by a of the the of all the and and these a of and lung were a and from the lungs were to and from lung, were of were to and and A was to the the of the by and from were the of from were and to a for for transgenic and mice were to the of the on was as an of the of the primary septa. was to alveolar as P P R C JA overexpression of in the to and Clin Invest. PubMed Scopus Google Scholar but the were that the were on the of the from were and to a for for transgenic and mice were to the of the on of the PDGF-B gene was to the lung by PDGF-B from a from the of the human gene JA human pulmonary surfactant Biol Chem. 1988; 263: Full Text PDF PubMed Google Scholar has been demonstrated to expression of to lung including alveolar and of the JA from human surfactant protein gene cell in transgenic J Google Scholar, JA from the human gene expression in the of transgenic PubMed Scopus Google Scholar The PDGF-B the PDGF-B and from the gene was of the PDGF-B this has been to the of expression of in transgenic can expression of in Natl Acad Sci USA. 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The lungs a that was by macrophages and in in were macrophages and cell of were observed pathology in adult SPC-PDGFB mice from the lineage. are from the lungs of SPC-PDGFB transgenic mice of the lineage. from a lung airspaces, inflammation, and can be lesions in a of macrophages and in a by in same as and of and in a of was by normal lung of which can be transgenic in which the lung normal by B, and and Mice from the developed a similar pattern of lung but in were as as the mice exhibited pathology throughout the lung that was characterized by enlarged airspaces, inflammation, and fibrosis. mice developed fibrotic lesions but inflammation and of the lungs by macrophages and was observed and mice a pathology was observed that was characterized by focal by normal lung lesions were observed in of transgenic mice exhibited of the pathology and normal by The phenotype observed in the was enlarged in a of the and fibrotic lesions were frequently mice exhibited lungs all of the have observed in the of age. indicated that expression of PDGF lung but was of the phenotype induced by the SPC-PDGFB in the lineage. A of lungs from mice of different was to the lung disease age. the of disease in lung from mice of different lung pathology was found in a of transgenic mice of but in mice of to two one in which the of the lung was by and one in which the lung was normal transgenic mice of all mice exhibited to and normal lung were are the of two of mice that in the of lung disease that is to the effects of the an age. The is to disease young but the disease in Because young transgenic mice lung of PDGF-B was to the was throughout SPC-PDGFB was observed in from mice in transgenic lungs the was the same of normal of transgenic lung that PDGF-B was in alveolar and in macrophages of PDGF-B was observed in in thickened fibrotic of lung, PDGF-B was observed in cells, and in within the thickened The observed in macrophages PDGF-B by macrophages of PDGF from we observed a transgenic that developed lung pathology by of that mice lung disease abnormalities in lung lung from and from of transgenic mice were and exhibited a pathology similar to that observed in adult including enlarged airspaces, inflammation, and from of SPC-PDGFB mice were but the pathology from that in of mice are in the of the by primary septa. growth to the saccules SPC-PDGFB mice to have enlarged saccules and thickened primary but inflammation was observed to in which was in the lung, mice to have enlarged To these changes were to lungs from SPC-PDGFB mice lungs from and a that were significantly in the transgenic lungs indicated that in transgenic mice that were to expression lung development that an lung was the of from SPC-PDGFB and were in lungs from transgenic and mice for as in and The are as and were significantly in the lungs from the transgenic mice transgenic that enlarged have been H Willetts K Pekny M Leveen P Lindahl P Hedstrand H Pekna M Hellstrom M Gebre-Medhin S Schalling M Nilsson M Kurland S Tornell J Heath JK Betsholtz C PDGF-A signaling is a critical event in lung alveolar myofibroblast development.Cell. 1996; 85: 863-873Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar, JA lung and in transgenic mice growth J Google Scholar The in of these mice was found to from a in growth that normal Because to be to this and are in PDGF-A H Willetts K Pekny M Leveen P Lindahl P Hedstrand H Pekna M Hellstrom M Gebre-Medhin S Schalling M Nilsson M Kurland S Tornell J Heath JK Betsholtz C PDGF-A signaling is a critical event in lung alveolar myofibroblast development.Cell. 1996; 85: 863-873Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar and in was the normal of the of in both and transgenic to be a of as has been in PDGF-A H Willetts K Pekny M Leveen P Lindahl P Hedstrand H Pekna M Hellstrom M Gebre-Medhin S Schalling M Nilsson M Kurland S Tornell J Heath JK Betsholtz C PDGF-A signaling is a critical event in lung alveolar myofibroblast development.Cell. 1996; 85: 863-873Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar and in transgenic mice growth JA lung and in transgenic mice growth J Google Scholar indicated that the of can in SPC-PDGFB mice and that of this is to the lesions observed in the transgenic A PDGF expression and lung has been both in human disease and in in the was to the expression of PDGF in the lung to the of this factor to pathology pulmonary PDGF be a potent mitogen for lung that during that one of PDGF overexpression in lung be lung fibrosis. SPC-PDGFB mice developed of that to and the focal of the that PDGF overexpression by but that were to the fibrotic SPC-PDGFB inflammation was observed within to fibrotic is from human lung disease and in in which inflammation to be a event in the development of pulmonary fibrosis. studies in which different were to PDGF in the lungs of we observed in SPC-PDGFB transgenic H S P S J Platelet-derived growth factor pulmonary cell proliferation and in J 1996; Google Scholar, M J S K S M S T A induced by overexpression of the growth factor platelet-derived growth factor B Natl Acad Sci USA. PubMed Scopus Google Scholar of PDGF-B from an was to M J S K S M S T A induced by overexpression of the growth factor platelet-derived growth factor B Natl Acad Sci USA. PubMed Scopus Google Scholar of human produced that was and H S P S J Platelet-derived growth factor pulmonary cell proliferation and in J 1996; Google Scholar The of this is to be by the of of the The these and be by the of the of PDGF to which the lungs were changes in PDGF expression signaling that have occurred in transgenic mice of PDGF to SPC-PDGFB mice developed enlarged phenotype was observed in both and adult mice but was different in these two the lungs of SPC-PDGFB mice exhibited enlarged saccules and thickened primary septa. in these mice was that in and the to be the adult SPC-PDGFB enlarged were but in mice these were and were of normal lung The by which PDGF-B expression produced this phenotype are PDGF-B expression to the of in that were observed in lungs from SPC-PDGFB in human lungs to from in the and to the of particularly a of alveolar and in the that of to the phenotype in SPC-PDGFB is studies in that have demonstrated the of expression by in cell expression in arterial smooth muscle on phenotype and is by PubMed Scopus Google Scholar, P and are for the and effects of growth factor and platelet-derived growth for smooth muscle Biol Chem. PubMed Scopus Google Scholar, H S Platelet-derived growth and and gene expression differentially in human Google Scholar has been a observed phenotype in transgenic mice pulmonary of and growth factor Mice deficient in PDGF-A H Willetts K Pekny M Leveen P Lindahl P Hedstrand H Pekna M Hellstrom M Gebre-Medhin S Schalling M Nilsson M Kurland S Tornell J Heath JK Betsholtz C PDGF-A signaling is a critical event in lung alveolar myofibroblast development.Cell. 1996; 85: 863-873Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar mice from the JA lung and in transgenic mice growth J Google Scholar, JA cell expression of human growth lung in transgenic Clin Invest. 1994; PubMed Scopus Google Scholar and mice from the cell protein P P R C JA overexpression of in the to and Clin Invest. PubMed Scopus Google Scholar, T P R JA expression of in the and Clin Invest. 1996; PubMed Scopus Google Scholar all developed enlarged as a of these all of these the enlarged have been to as a of abnormalities in lung The lungs of PDGF-A mice were normal but developed enlarged the as a of H Willetts K Pekny M Leveen P Lindahl P Hedstrand H Pekna M Hellstrom M Gebre-Medhin S Schalling M Nilsson M Kurland S Tornell J Heath JK Betsholtz C PDGF-A signaling is a critical event in lung alveolar myofibroblast development.Cell. 1996; 85: 863-873Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar Neonatal lungs from transgenic mice to have enlarged saccules and developed enlarged the growth of JA lung and in transgenic mice growth J Google Scholar mice in which the was throughout lung development exhibited but mice in which expression was induced this P P R C JA overexpression of in the to and Clin Invest. PubMed Scopus Google Scholar that is a of throughout development that and of this in of a number of including of a growth factor that mesenchymal cell in the of enlarged in that PDGF is an important growth factor in lung of PDGF-A and and and receptors has been in the developing lung, PDGF-A expression has been in C P M Platelet-derived growth and in during PubMed Scopus (60) Google Scholar, P L Hellstrom M Gebre-Medhin S Willetts K Heath JK Betsholtz C in mice is to of of alveolar smooth muscle cell during lung PubMed Google Scholar, A P Platelet-derived growth and its are in but cell of the Google Scholar and PDGF-B expression has been in and C P M Platelet-derived growth and in during PubMed Scopus (60) Google Scholar, P L Hellstrom M Gebre-Medhin S Willetts K Heath JK Betsholtz C in mice is to of of alveolar smooth muscle cell during lung PubMed Google Scholar is in mesenchymal and P L Hellstrom M Gebre-Medhin S Willetts K Heath JK Betsholtz C in mice is to of of alveolar smooth muscle cell during lung PubMed Google Scholar, A P Platelet-derived growth and its are in but cell of the Google Scholar and is in mesenchymal P L Hellstrom M Gebre-Medhin S Willetts K Heath JK Betsholtz C in mice is to of of alveolar smooth muscle cell during lung PubMed Google Scholar expression are PDGF isoforms as signaling that lung mesenchymal cell proliferation and PDGF-A has been to be for normal lung of the PDGF-A gene by homologous an lung H Willetts K Pekny M Leveen P Lindahl P Hedstrand H Pekna M Hellstrom M Gebre-Medhin S Schalling M Nilsson M Kurland S Tornell J Heath JK Betsholtz C PDGF-A signaling is a critical event in lung alveolar myofibroblast development.Cell. 1996; 85: 863-873Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar The lungs of PDGF-A mice were normal but developed enlarged within the The in these mice was found to be the of mesenchymal that are for growth and the of P L Hellstrom M Gebre-Medhin S Willetts K Heath JK Betsholtz C in mice is to of of alveolar smooth muscle cell during lung PubMed Google Scholar SPC-PDGFB mice exhibited an lung phenotype on the of on the of PDGF this phenotype is to from the of PDGF-B that is by alveolar and to PDGF receptors on mesenchymal in the lung that the thickened in SPC-PDGFB mice from mesenchymal cell proliferation by and that the enlarged as a of an and mesenchymal cell macrophages and was observed in the lungs of SPC-PDGFB transgenic was throughout the lung but was confined to focal areas. focal of inflammation were usually within to of indicated an inflammation and of the but these were related was the of inflammation, macrophages were confined to the were observed both within the and in the is the are the as a of the that to the The of was of this cell has been implicated as a role in the pathogenesis of lung K M B lung and in pulmonary fibrosis.J Google Scholar The expression of and the of in a of lung K M B lung and in pulmonary fibrosis.J Google Scholar we observed a inflammation and in SPC-PDGFB studies be to a and the pathogenesis of in SPC-PDGFB by which PDGF expression an The be a of PDGF on of PDGF receptors on macrophages has been demonstrated but is that PDGF can as a factor for but normal are by platelet-derived growth factor (PDGF) J 1996; Scholar A by which PDGF inflammation is the of in mesenchymal that can to that this can from studies in in which PDGF of expression of including the of gene by platelet-derived growth factor.Cell. Full Text PDF PubMed Scopus Google Scholar PDGF can of lung as the of a pulmonary The of lung disease that was observed in SPC-PDGFB mice varied significantly among individual mice within the same transgenic lineage. mice exhibited enlarged saccules and thickened but the lungs of transgenic mice young to of mice normal lung were by mice were by and focal of inflammation and fibrosis. SPC-PDGFB mice and of in the lung, but varied in the of the lung that was are the of two of SPC-PDGFB is to PDGF-B overexpression during lung mice have lungs and lung disease as young The is to the effects of PDGF-B mice have normal lungs have normal lungs as young and lung disease are of age. that this in phenotype is a in expression among individual in expression within a of transgenic lungs for PDGF-B indicated in both normal and of the lung, the was similar in alveolar of inflammation, PDGF-B was observed in but was this PDGF by macrophages PDGF that been by the in PDGF expression as a factor for in lung disease. this for the of two of mice disease in PDGF expression be to in a of the disease phenotype the observed two distinct is that among mice within the is for the in The SPC-PDGFB transgenic mice were and on a that is a of two and these in the of the lung to mice a and from the expression of that the to such as PDGF signaling induced by in to lung and disease produced by such as L J A M of and the of receptors in lung in PubMed Scopus Google Scholar, pulmonary of and protein in and of Google Scholar and and expression in the lungs of mice that to lesions to J Full Text Full Text PDF PubMed Scopus Google Scholar have been these the of and to and growth in the lung to be important in the to fibrotic in pulmonary PubMed Scopus Google Scholar is for that the and to PDGF PDGF overexpression in lung in enlarged airspaces, inflammation, and fibrosis. the to from abnormalities that occurred both and in the severity of lung disease that the of the mice be important in the of the lung to PDGF the of PDGF in lung development and disease studies PDGF overexpression mice to lung induced by such as for and for