Distinct patterns of pulmonary injury and fibrosis induced by intratracheal and subcutaneous bleomycin in the mouse

Relevance for distinct forms of human lung fibrosis

Anna P. Lam, Erica L. Herzog, Denisa Melichian, Joseph Sennello, Ye Gan, Kirtee Raparia, Robert Homer, Anjana Yeldandi, John Varga*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Citations (Scopus)

Abstract

Background: Murine models can be useful for understanding complex diseases such as pulmonary fibrosis. Bleomycin, administered via a wide variety of routes, is commonly used to induce lung fibrosis in rodents. We compared fibrotic responses in the lung elicited by bleomycin given by subcutaneous injection and intratracheal administration. Mice were treated with one dose of intratracheal bleomycin or with subcutaneous bleomycin daily for 14 days. Lungs and skin were analyzed for fibrosis by histopathology and immunostaining for alpha-smooth muscle actin, and transforming growth factor-beta protein level and apoptosis were evaluated. Results: While intratracheal and subcutaneous approaches yielded comparable severity of pulmonary fibrosis, distinct spatial and temporal evolution of pulmonary changes was noted. Intratracheal bleomycin induced early onset and rapid resolution of inflammation, while subcutaneous bleomycin caused more sustained lung inflammation with slow resolution of injury. Moreover, subcutaneous bleomcyin caused a predominantly peri-vascular pattern of lung fibrosis, whereas intratracheal instillation of bleomycin additionally caused injury around the airways. Early apoptotic responses were primarily centered around the airways in mice given intratracheal bleomycin but were seen around blood vessels with subcutaneous bleomycin. Conclusions: Subcutaneous administration of bleomycin causes a pattern of lung injury and fibrosis that is histologically distinct from that induced by the intratracheal route. These two distinct modes of bleomycin delivery might have utility for modeling interstitial lung disease associated with airway injury, such as idiopathic pulmonary fibrosis, versus systemic autoimmunity, such as systemic sclerosis.

Original languageEnglish (US)
Title of host publicationCystic and Idiopathic Pulmonary Fibrosis
Subtitle of host publicationRisk Factors, Management and Long-Term Health Outcomes
PublisherNova Science Publishers, Inc.
Pages127-152
Number of pages26
ISBN (Electronic)9781634855488
ISBN (Print)9781634855082
StatePublished - Jan 1 2016

Fingerprint

Pulmonary Fibrosis
Bleomycin
Lung Injury
Fibrosis
Lung
Blood Vessels
Wounds and Injuries
indium-bleomycin
Idiopathic Pulmonary Fibrosis
Systemic Scleroderma
Interstitial Lung Diseases
Subcutaneous Injections
Autoimmunity
Transforming Growth Factor beta
Smooth Muscle
Actins
Rodentia
Pneumonia
Apoptosis
Inflammation

Keywords

  • Bleomycin
  • Fibrosis
  • Idiopathic pulmonary fibrosis
  • Intratracheal
  • Mouse model
  • Subcutaneous
  • Systemic sclerosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lam, A. P., Herzog, E. L., Melichian, D., Sennello, J., Gan, Y., Raparia, K., ... Varga, J. (2016). Distinct patterns of pulmonary injury and fibrosis induced by intratracheal and subcutaneous bleomycin in the mouse: Relevance for distinct forms of human lung fibrosis. In Cystic and Idiopathic Pulmonary Fibrosis: Risk Factors, Management and Long-Term Health Outcomes (pp. 127-152). Nova Science Publishers, Inc..
Lam, Anna P. ; Herzog, Erica L. ; Melichian, Denisa ; Sennello, Joseph ; Gan, Ye ; Raparia, Kirtee ; Homer, Robert ; Yeldandi, Anjana ; Varga, John. / Distinct patterns of pulmonary injury and fibrosis induced by intratracheal and subcutaneous bleomycin in the mouse : Relevance for distinct forms of human lung fibrosis. Cystic and Idiopathic Pulmonary Fibrosis: Risk Factors, Management and Long-Term Health Outcomes. Nova Science Publishers, Inc., 2016. pp. 127-152
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abstract = "Background: Murine models can be useful for understanding complex diseases such as pulmonary fibrosis. Bleomycin, administered via a wide variety of routes, is commonly used to induce lung fibrosis in rodents. We compared fibrotic responses in the lung elicited by bleomycin given by subcutaneous injection and intratracheal administration. Mice were treated with one dose of intratracheal bleomycin or with subcutaneous bleomycin daily for 14 days. Lungs and skin were analyzed for fibrosis by histopathology and immunostaining for alpha-smooth muscle actin, and transforming growth factor-beta protein level and apoptosis were evaluated. Results: While intratracheal and subcutaneous approaches yielded comparable severity of pulmonary fibrosis, distinct spatial and temporal evolution of pulmonary changes was noted. Intratracheal bleomycin induced early onset and rapid resolution of inflammation, while subcutaneous bleomycin caused more sustained lung inflammation with slow resolution of injury. Moreover, subcutaneous bleomcyin caused a predominantly peri-vascular pattern of lung fibrosis, whereas intratracheal instillation of bleomycin additionally caused injury around the airways. Early apoptotic responses were primarily centered around the airways in mice given intratracheal bleomycin but were seen around blood vessels with subcutaneous bleomycin. Conclusions: Subcutaneous administration of bleomycin causes a pattern of lung injury and fibrosis that is histologically distinct from that induced by the intratracheal route. These two distinct modes of bleomycin delivery might have utility for modeling interstitial lung disease associated with airway injury, such as idiopathic pulmonary fibrosis, versus systemic autoimmunity, such as systemic sclerosis.",
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author = "Lam, {Anna P.} and Herzog, {Erica L.} and Denisa Melichian and Joseph Sennello and Ye Gan and Kirtee Raparia and Robert Homer and Anjana Yeldandi and John Varga",
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Lam, AP, Herzog, EL, Melichian, D, Sennello, J, Gan, Y, Raparia, K, Homer, R, Yeldandi, A & Varga, J 2016, Distinct patterns of pulmonary injury and fibrosis induced by intratracheal and subcutaneous bleomycin in the mouse: Relevance for distinct forms of human lung fibrosis. in Cystic and Idiopathic Pulmonary Fibrosis: Risk Factors, Management and Long-Term Health Outcomes. Nova Science Publishers, Inc., pp. 127-152.

Distinct patterns of pulmonary injury and fibrosis induced by intratracheal and subcutaneous bleomycin in the mouse : Relevance for distinct forms of human lung fibrosis. / Lam, Anna P.; Herzog, Erica L.; Melichian, Denisa; Sennello, Joseph; Gan, Ye; Raparia, Kirtee; Homer, Robert; Yeldandi, Anjana; Varga, John.

Cystic and Idiopathic Pulmonary Fibrosis: Risk Factors, Management and Long-Term Health Outcomes. Nova Science Publishers, Inc., 2016. p. 127-152.

Research output: Chapter in Book/Report/Conference proceedingChapter

TY - CHAP

T1 - Distinct patterns of pulmonary injury and fibrosis induced by intratracheal and subcutaneous bleomycin in the mouse

T2 - Relevance for distinct forms of human lung fibrosis

AU - Lam, Anna P.

AU - Herzog, Erica L.

AU - Melichian, Denisa

AU - Sennello, Joseph

AU - Gan, Ye

AU - Raparia, Kirtee

AU - Homer, Robert

AU - Yeldandi, Anjana

AU - Varga, John

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Background: Murine models can be useful for understanding complex diseases such as pulmonary fibrosis. Bleomycin, administered via a wide variety of routes, is commonly used to induce lung fibrosis in rodents. We compared fibrotic responses in the lung elicited by bleomycin given by subcutaneous injection and intratracheal administration. Mice were treated with one dose of intratracheal bleomycin or with subcutaneous bleomycin daily for 14 days. Lungs and skin were analyzed for fibrosis by histopathology and immunostaining for alpha-smooth muscle actin, and transforming growth factor-beta protein level and apoptosis were evaluated. Results: While intratracheal and subcutaneous approaches yielded comparable severity of pulmonary fibrosis, distinct spatial and temporal evolution of pulmonary changes was noted. Intratracheal bleomycin induced early onset and rapid resolution of inflammation, while subcutaneous bleomycin caused more sustained lung inflammation with slow resolution of injury. Moreover, subcutaneous bleomcyin caused a predominantly peri-vascular pattern of lung fibrosis, whereas intratracheal instillation of bleomycin additionally caused injury around the airways. Early apoptotic responses were primarily centered around the airways in mice given intratracheal bleomycin but were seen around blood vessels with subcutaneous bleomycin. Conclusions: Subcutaneous administration of bleomycin causes a pattern of lung injury and fibrosis that is histologically distinct from that induced by the intratracheal route. These two distinct modes of bleomycin delivery might have utility for modeling interstitial lung disease associated with airway injury, such as idiopathic pulmonary fibrosis, versus systemic autoimmunity, such as systemic sclerosis.

AB - Background: Murine models can be useful for understanding complex diseases such as pulmonary fibrosis. Bleomycin, administered via a wide variety of routes, is commonly used to induce lung fibrosis in rodents. We compared fibrotic responses in the lung elicited by bleomycin given by subcutaneous injection and intratracheal administration. Mice were treated with one dose of intratracheal bleomycin or with subcutaneous bleomycin daily for 14 days. Lungs and skin were analyzed for fibrosis by histopathology and immunostaining for alpha-smooth muscle actin, and transforming growth factor-beta protein level and apoptosis were evaluated. Results: While intratracheal and subcutaneous approaches yielded comparable severity of pulmonary fibrosis, distinct spatial and temporal evolution of pulmonary changes was noted. Intratracheal bleomycin induced early onset and rapid resolution of inflammation, while subcutaneous bleomycin caused more sustained lung inflammation with slow resolution of injury. Moreover, subcutaneous bleomcyin caused a predominantly peri-vascular pattern of lung fibrosis, whereas intratracheal instillation of bleomycin additionally caused injury around the airways. Early apoptotic responses were primarily centered around the airways in mice given intratracheal bleomycin but were seen around blood vessels with subcutaneous bleomycin. Conclusions: Subcutaneous administration of bleomycin causes a pattern of lung injury and fibrosis that is histologically distinct from that induced by the intratracheal route. These two distinct modes of bleomycin delivery might have utility for modeling interstitial lung disease associated with airway injury, such as idiopathic pulmonary fibrosis, versus systemic autoimmunity, such as systemic sclerosis.

KW - Bleomycin

KW - Fibrosis

KW - Idiopathic pulmonary fibrosis

KW - Intratracheal

KW - Mouse model

KW - Subcutaneous

KW - Systemic sclerosis

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BT - Cystic and Idiopathic Pulmonary Fibrosis

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Lam AP, Herzog EL, Melichian D, Sennello J, Gan Y, Raparia K et al. Distinct patterns of pulmonary injury and fibrosis induced by intratracheal and subcutaneous bleomycin in the mouse: Relevance for distinct forms of human lung fibrosis. In Cystic and Idiopathic Pulmonary Fibrosis: Risk Factors, Management and Long-Term Health Outcomes. Nova Science Publishers, Inc. 2016. p. 127-152