Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis

Degryse, Amber L.; Tanjore, Harikrishna; Xu, Xiaochuan C.; Polosukhin, Vasiliy V.; Jones, Brittany R.; McMahon, Frank B.; Gleaves, Linda A.; Blackwell, Timothy S.; Lawson, William

doi:10.1152/ajplung.00026.2010

Cited by 245 publications

(268 citation statements)

References 43 publications

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“…We have previously shown that the number of TUNEL+ epithelial cells peaks in the lungs at 1 wk after i.t. bleomycin injection (17). At this time point, lung sections from L188Q SFTPC mice showed greater numbers of TUNEL+ AECs than lungs from WT controls did (Fig.…”

Section: Expression Of L188q Sftpc Increases Aec Apoptosis After Bleomentioning

confidence: 74%

“…3D). In previous studies, we have used S100A4 as a fibroblast marker in the lungs (14)(15)(16)(17). Therefore, we evaluated lung sections by IHC for S100A4 expression and noted greater numbers of S100A4-positive fibroblasts in L188Q SFTPC mice compared with WT controls after bleomycin treatment ( Additionally, we wanted to determine whether lung mechanics were different at 3 wk after bleomycin treatment in L188Q SFTPC mice.…”

Section: Resultsmentioning

confidence: 99%

“…Bleomycin (0.04 unit) (Bedford Laboratories) was injected i.t. in mice by intubation as previously described (17). Lungs were harvested for histology, frozen tissue, bronchoalveolar lavage, or cell isolation as previously described (14)(15)(16)(17).…”

Section: Methodsmentioning

confidence: 99%

“…Formalin-fixed lung sections were prepared as previously described (14)(15)(16). IHC (14,15), immunofluorescence (16,17), TUNEL (15,17), and bronchoalveolar lavage with cell counts (15,17) were performed as previously described. RNA isolation, real-time RT-PCR, and Western blot analysis were performed by using standard techniques (detailed in SI Materials and Methods).…”

Section: Methodsmentioning

confidence: 99%

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Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs

Lawson

Cheng

Degryse

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Evidence of endoplasmic reticulum (ER) stress has been found in lungs of patients with familial and sporadic idiopathic pulmonary fibrosis. We tested whether ER stress causes or exacerbates lung fibrosis by ( i ) conditional expression of a mutant form of surfactant protein C (L188Q SFTPC ) found in familial interstitial pneumonia and ( ii ) intratracheal treatment with the protein misfolding agent tunicamycin. We developed transgenic mice expressing L188Q SFTPC exclusively in type II alveolar epithelium by using the Tet-On system. Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis was identified in the absence of a second profibrotic stimulus. After intratracheal bleomycin, L188Q SFTPC -expressing mice developed exaggerated lung fibrosis and reduced static lung compliance compared with controls. Bleomycin-treated L188Q SFTPC mice also demonstrated increased apoptosis of alveolar epithelial cells and greater numbers of fibroblasts in the lungs. With a complementary model, intratracheal tunicamycin treatment failed to induce lung remodeling yet resulted in augmentation of bleomycin-induced fibrosis. These data support the concept that ER stress produces a dysfunctional epithelial cell phenotype that facilitates fibrotic remodeling. ER stress pathways may serve as important therapeutic targets in idiopathic pulmonary fibrosis.

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Section: Expression Of L188q Sftpc Increases Aec Apoptosis After Bleomentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs

Lawson

Cheng

Degryse

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

327

307

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“…Three sections per mouse were measured. On lung sections, fibrosis development was scored as previously described (22). Average scores were calculated by scoring 3 different fields of view per slide, and 2 slides per lung were scored in a blinded manner.…”

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confidence: 99%

Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

Lambrecht

Smith

Wilde

et al. 2014

Arthritis & Rheumatology

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ObjectiveTransforming growth factor β superfamily members are involved in the pathogenesis of systemic sclerosis (SSc). Growth differentiation factor 15 (GDF‐15) is a distant member of this family. We undertook this study to evaluate the role of GDF‐15 in SSc pathogenesis.MethodsA longitudinal prospective cohort of SSc patients was screened for serum GDF‐15 levels using enzyme‐linked immunosorbent assay, and associations with clinical data were analyzed. In vitro stimulation experiments were performed on lung fibroblasts. The role of GDF‐15 in fibrosis development in vivo was evaluated in the bleomycin lung fibrosis model in GDF‐15–deficient mice.ResultsGDF‐15 was measured at baseline in serum samples from 119 SSc patients. An increase in GDF‐15 levels was observed in patients classified as having no skin involvement, those with limited cutaneous SSc, and those with diffuse cutaneous SSc. Moreover, baseline serum GDF‐15 levels correlated strongly with disease activity and extent of organ involvement, particularly clinical symptoms of lung fibrosis, including impact on lung function at prospective followup. This was mimicked in the bleomycin model of SSc, in which animals exposed to bleomycin had elevated expression levels of GDF‐15 in lung tissue. Lung fibroblasts isolated from GDF‐15–deficient mice showed reduced induction of interleukin‐6 and CCL2 upon bleomycin stimulation. Surprisingly, no differences in fibrosis development were observed between wild‐type and GDF‐15–deficient animals.ConclusionAn intriguing profile of serum GDF‐15 levels was found in SSc patients. GDF‐15 expression is induced during fibrosis development and markedly correlates with lung function impairment in this disease. The protein may participate in fibrosis initiation, but is not indispensable in the course of fibrosis development in vivo.

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First magnetic particle imaging to assess pulmonary vascular leakage in vivo in the acutely injured and fibrotic lung

Feng,

Gao,

et al. 2023

Bioengineering & Transla Med

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Increased pulmonary vascular permeability is a characteristic feature of lung injury. However, there are no established methods that allow the three‐dimensional visualization and quantification of pulmonary vascular permeability in vivo. Evans blue extravasation test and total protein test of bronchoalveolar lavage fluid (BALF) are permeability assays commonly used in research settings. However, they lack the ability to identify the spatial and temporal heterogeneity of endothelial barrier disruption, which is typical in lung injuries. Magnetic resonance (MR) and near‐infrared (NIR) imaging have been proposed to image pulmonary permeability, but suffer from limited sensitivity and penetration depth, respectively. In this study, we report the first use of magnetic particle imaging (MPI) to assess pulmonary vascular leakage noninvasively in vivo in mice. A dextran‐coated superparamagnetic iron oxide (SPIO), synomag®, was employed as the imaging tracer, and pulmonary SPIO extravasation was imaged and quantified to evaluate the vascular leakage. Animal models of acute lung injury and pulmonary fibrosis (PF) were used to validate the proposed method. MPI sensitively detected the SPIO extravasation in both acutely injured and fibrotic lungs in vivo, which was confirmed by ex vivo imaging and Prussian blue staining. Moreover, 3D MPI illustrated the spatial heterogeneity of vascular leakage, which correlated well with CT findings. Based on the in vivo 3D MPI images, we defined the SPIO extravasation index (SEI) to quantify the vascular leakage. A significant increase in SEI was observed in the injured lungs, in consistent with the results obtained via ex vivo permeability assays. Overall, our results demonstrate that 3D quantitative MPI serves as a useful tool to examine pulmonary vascular integrity in vivo, which shows promise for future clinical translation.

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Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis

Cited by 245 publications

References 43 publications

Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs

Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs

Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

First magnetic particle imaging to assess pulmonary vascular leakage in vivo in the acutely injured and fibrotic lung

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