Development of pulmonary fibrosis in fibrinogen-deficient mice

Julie A. Wilberding, Victoria A. Ploplis, Laura McLennan, Zhong Liang, Ivo Cornelissen, Matthew Feldman, Melanie E. Deford, Elliot Rosen, Francis J. Castellino

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Bleomycin is an antineoplastic drug commonly used for the treatment of many carcinomas and lymphomas. Its toxic side effect on hung tissue is a major limitation to its use, with approximately 3-5% of patients affected. Although the number of affected patients is small, the damage incurred by bleomycin in these patients is often irreversible and, at times, fatal. A number of therapies have been shown to be effective in animal studies to minimize damage, but to date no "magic bullet" has been identified. Many proteins of the fibrinolytic system have been implicated as playing a role in the progression of the disease, one of which is fibrinogen (Fg) acting in the context of a fibroproliferative agent. Its presence correlates with an upregulation of plasminogen activator inhibitor-1 and tissue factor in alveolar cells surrounding the lesion area. It is believed that Fg participates in the activation and migration of fibroblasts and provides a scaffold, in the form of fibrin, for cell migration following induction of acute lung injury. To further understand the mechanism of injury following bleomycin treatment and the possible role of fibrinogen therein, mice have been generated with a targeted deletion of the gamma-chain of Fg, which resulted in the absence of detectable circulating Fg. The offsprings of Fg heterozygous mice (FG+/-) mice follow Mendelian distributions indicating no embryonic lethality with this deletion. Approximately one-half of the Fg-deficient (FG-/-) neonates exhibited bleeding episodes, approximately one-half of which were fatal. For the pulmonary fibrosis study, FG-/- mice and wildtype littermates were administered a bleomycin solution intratracheally and the disease was allowed to progress for two weeks. The mice were then sacrificed, the left lung was excised for hydroxyproline analysis, the right lung was processed for histologic profiling. Examination of trichrome stained sections, surprisingly, revealed no qualitative difference between wildtype and FG-/-animals. The extent and pattern of the deposition of collagen were also similar. These results were quantitatively confirmed by hydroxyproline analysis, which revealed equivalent increases in collagen content between wildtype and FG-/- animals when compared to appropriate saline controls. Analysis of the early acute inflammatory stage of the disease showed a difference in the neutrophil population between days three and five of the disease. These studies suggest that, although fibrinogen is not required for collagen deposition at the later stage of the disease, it may play a role in the early acute inflammation stage.

Original languageEnglish (US)
Pages (from-to)542-548
Number of pages7
JournalAnnals of the New York Academy of Sciences
Volume936
StatePublished - 2001
Externally publishedYes

Fingerprint

Pulmonary Fibrosis
Fibrinogen
Bleomycin
Animals
Collagen
Hydroxyproline
Alveolar Epithelial Cells
Lung
Magic
Forms (concrete)
Acute Lung Injury
Poisons
Plasminogen Activator Inhibitor 1
Thromboplastin
Fibroblasts
Mouse
Fibrin
Scaffolds
Antineoplastic Agents
Cell Movement

Keywords

  • Fibrinogen-deficient mice
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wilberding, J. A., Ploplis, V. A., McLennan, L., Liang, Z., Cornelissen, I., Feldman, M., ... Castellino, F. J. (2001). Development of pulmonary fibrosis in fibrinogen-deficient mice. Annals of the New York Academy of Sciences, 936, 542-548.

Development of pulmonary fibrosis in fibrinogen-deficient mice. / Wilberding, Julie A.; Ploplis, Victoria A.; McLennan, Laura; Liang, Zhong; Cornelissen, Ivo; Feldman, Matthew; Deford, Melanie E.; Rosen, Elliot; Castellino, Francis J.

In: Annals of the New York Academy of Sciences, Vol. 936, 2001, p. 542-548.

Research output: Contribution to journalArticle

Wilberding, JA, Ploplis, VA, McLennan, L, Liang, Z, Cornelissen, I, Feldman, M, Deford, ME, Rosen, E & Castellino, FJ 2001, 'Development of pulmonary fibrosis in fibrinogen-deficient mice', Annals of the New York Academy of Sciences, vol. 936, pp. 542-548.
Wilberding JA, Ploplis VA, McLennan L, Liang Z, Cornelissen I, Feldman M et al. Development of pulmonary fibrosis in fibrinogen-deficient mice. Annals of the New York Academy of Sciences. 2001;936:542-548.
Wilberding, Julie A. ; Ploplis, Victoria A. ; McLennan, Laura ; Liang, Zhong ; Cornelissen, Ivo ; Feldman, Matthew ; Deford, Melanie E. ; Rosen, Elliot ; Castellino, Francis J. / Development of pulmonary fibrosis in fibrinogen-deficient mice. In: Annals of the New York Academy of Sciences. 2001 ; Vol. 936. pp. 542-548.
@article{a86d841d56254a2b891699a5ee64b660,
title = "Development of pulmonary fibrosis in fibrinogen-deficient mice",
abstract = "Bleomycin is an antineoplastic drug commonly used for the treatment of many carcinomas and lymphomas. Its toxic side effect on hung tissue is a major limitation to its use, with approximately 3-5{\%} of patients affected. Although the number of affected patients is small, the damage incurred by bleomycin in these patients is often irreversible and, at times, fatal. A number of therapies have been shown to be effective in animal studies to minimize damage, but to date no {"}magic bullet{"} has been identified. Many proteins of the fibrinolytic system have been implicated as playing a role in the progression of the disease, one of which is fibrinogen (Fg) acting in the context of a fibroproliferative agent. Its presence correlates with an upregulation of plasminogen activator inhibitor-1 and tissue factor in alveolar cells surrounding the lesion area. It is believed that Fg participates in the activation and migration of fibroblasts and provides a scaffold, in the form of fibrin, for cell migration following induction of acute lung injury. To further understand the mechanism of injury following bleomycin treatment and the possible role of fibrinogen therein, mice have been generated with a targeted deletion of the gamma-chain of Fg, which resulted in the absence of detectable circulating Fg. The offsprings of Fg heterozygous mice (FG+/-) mice follow Mendelian distributions indicating no embryonic lethality with this deletion. Approximately one-half of the Fg-deficient (FG-/-) neonates exhibited bleeding episodes, approximately one-half of which were fatal. For the pulmonary fibrosis study, FG-/- mice and wildtype littermates were administered a bleomycin solution intratracheally and the disease was allowed to progress for two weeks. The mice were then sacrificed, the left lung was excised for hydroxyproline analysis, the right lung was processed for histologic profiling. Examination of trichrome stained sections, surprisingly, revealed no qualitative difference between wildtype and FG-/-animals. The extent and pattern of the deposition of collagen were also similar. These results were quantitatively confirmed by hydroxyproline analysis, which revealed equivalent increases in collagen content between wildtype and FG-/- animals when compared to appropriate saline controls. Analysis of the early acute inflammatory stage of the disease showed a difference in the neutrophil population between days three and five of the disease. These studies suggest that, although fibrinogen is not required for collagen deposition at the later stage of the disease, it may play a role in the early acute inflammation stage.",
keywords = "Fibrinogen-deficient mice, Pulmonary fibrosis",
author = "Wilberding, {Julie A.} and Ploplis, {Victoria A.} and Laura McLennan and Zhong Liang and Ivo Cornelissen and Matthew Feldman and Deford, {Melanie E.} and Elliot Rosen and Castellino, {Francis J.}",
year = "2001",
language = "English (US)",
volume = "936",
pages = "542--548",
journal = "Annals of the New York Academy of Sciences",
issn = "0077-8923",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Development of pulmonary fibrosis in fibrinogen-deficient mice

AU - Wilberding, Julie A.

AU - Ploplis, Victoria A.

AU - McLennan, Laura

AU - Liang, Zhong

AU - Cornelissen, Ivo

AU - Feldman, Matthew

AU - Deford, Melanie E.

AU - Rosen, Elliot

AU - Castellino, Francis J.

PY - 2001

Y1 - 2001

N2 - Bleomycin is an antineoplastic drug commonly used for the treatment of many carcinomas and lymphomas. Its toxic side effect on hung tissue is a major limitation to its use, with approximately 3-5% of patients affected. Although the number of affected patients is small, the damage incurred by bleomycin in these patients is often irreversible and, at times, fatal. A number of therapies have been shown to be effective in animal studies to minimize damage, but to date no "magic bullet" has been identified. Many proteins of the fibrinolytic system have been implicated as playing a role in the progression of the disease, one of which is fibrinogen (Fg) acting in the context of a fibroproliferative agent. Its presence correlates with an upregulation of plasminogen activator inhibitor-1 and tissue factor in alveolar cells surrounding the lesion area. It is believed that Fg participates in the activation and migration of fibroblasts and provides a scaffold, in the form of fibrin, for cell migration following induction of acute lung injury. To further understand the mechanism of injury following bleomycin treatment and the possible role of fibrinogen therein, mice have been generated with a targeted deletion of the gamma-chain of Fg, which resulted in the absence of detectable circulating Fg. The offsprings of Fg heterozygous mice (FG+/-) mice follow Mendelian distributions indicating no embryonic lethality with this deletion. Approximately one-half of the Fg-deficient (FG-/-) neonates exhibited bleeding episodes, approximately one-half of which were fatal. For the pulmonary fibrosis study, FG-/- mice and wildtype littermates were administered a bleomycin solution intratracheally and the disease was allowed to progress for two weeks. The mice were then sacrificed, the left lung was excised for hydroxyproline analysis, the right lung was processed for histologic profiling. Examination of trichrome stained sections, surprisingly, revealed no qualitative difference between wildtype and FG-/-animals. The extent and pattern of the deposition of collagen were also similar. These results were quantitatively confirmed by hydroxyproline analysis, which revealed equivalent increases in collagen content between wildtype and FG-/- animals when compared to appropriate saline controls. Analysis of the early acute inflammatory stage of the disease showed a difference in the neutrophil population between days three and five of the disease. These studies suggest that, although fibrinogen is not required for collagen deposition at the later stage of the disease, it may play a role in the early acute inflammation stage.

AB - Bleomycin is an antineoplastic drug commonly used for the treatment of many carcinomas and lymphomas. Its toxic side effect on hung tissue is a major limitation to its use, with approximately 3-5% of patients affected. Although the number of affected patients is small, the damage incurred by bleomycin in these patients is often irreversible and, at times, fatal. A number of therapies have been shown to be effective in animal studies to minimize damage, but to date no "magic bullet" has been identified. Many proteins of the fibrinolytic system have been implicated as playing a role in the progression of the disease, one of which is fibrinogen (Fg) acting in the context of a fibroproliferative agent. Its presence correlates with an upregulation of plasminogen activator inhibitor-1 and tissue factor in alveolar cells surrounding the lesion area. It is believed that Fg participates in the activation and migration of fibroblasts and provides a scaffold, in the form of fibrin, for cell migration following induction of acute lung injury. To further understand the mechanism of injury following bleomycin treatment and the possible role of fibrinogen therein, mice have been generated with a targeted deletion of the gamma-chain of Fg, which resulted in the absence of detectable circulating Fg. The offsprings of Fg heterozygous mice (FG+/-) mice follow Mendelian distributions indicating no embryonic lethality with this deletion. Approximately one-half of the Fg-deficient (FG-/-) neonates exhibited bleeding episodes, approximately one-half of which were fatal. For the pulmonary fibrosis study, FG-/- mice and wildtype littermates were administered a bleomycin solution intratracheally and the disease was allowed to progress for two weeks. The mice were then sacrificed, the left lung was excised for hydroxyproline analysis, the right lung was processed for histologic profiling. Examination of trichrome stained sections, surprisingly, revealed no qualitative difference between wildtype and FG-/-animals. The extent and pattern of the deposition of collagen were also similar. These results were quantitatively confirmed by hydroxyproline analysis, which revealed equivalent increases in collagen content between wildtype and FG-/- animals when compared to appropriate saline controls. Analysis of the early acute inflammatory stage of the disease showed a difference in the neutrophil population between days three and five of the disease. These studies suggest that, although fibrinogen is not required for collagen deposition at the later stage of the disease, it may play a role in the early acute inflammation stage.

KW - Fibrinogen-deficient mice

KW - Pulmonary fibrosis

UR - http://www.scopus.com/inward/record.url?scp=0034964347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034964347&partnerID=8YFLogxK

M3 - Article

VL - 936

SP - 542

EP - 548

JO - Annals of the New York Academy of Sciences

JF - Annals of the New York Academy of Sciences

SN - 0077-8923

ER -