Experimental Models for the Study of Pulmonary Fibrosis: Current Usefulness and Future Promise

doi:10.1016/S1579-2129(07)60115-3

Archivos de Bronconeumología ((English Edition))

Volume 43, Issue 9, 2007, Pages 501-507

https://doi.org/10.1016/S1579-2129(07)60115-3 Get rights and content

Diffuse interstitial lung diseases form a group of respiratory diseases about which many questions remain to be answered. In recent years there have been major advances in the correct diagnostic classification of each disease, and therefore, the essential foundations have been laid for investigation of their pathophysiology. However, both the triggers and the precise mechanisms that lead to irreversible changes in the lung parenchyma remain to be identified. Idiopathic pulmonary fibrosis is the most common diffuse interstitial lung disease and has the worst prognosis. Current treatments are empirical and the response is random; furthermore, they do not improve survival. Consequently, most basic research has focused on the pathophysiology of the disease and on identifying an effective therapeutic approach. The aim of this review is to describe the experimental studies that have begun to open the way towards an understanding of the complex process of fibrosis.

Las enfermedades pulmonares intersticiales difusas son un grupo de enfermedades respiratorias con múltiples incógnitas por resolver. En los últimos años se ha asistido a un gran avance en la clasificación para el diagnóstico correcto de cada una de ellas, con lo que se han sentado las bases indispensables para el estudio del proceso fisiopatológico en cada entidad. Sin embargo, resultan desconocidos tanto la causa desencadenante como los mecanismos exactos que llevan a la alteración irreversible del parénquima. Dentro de las enfermedades pulmonares intersticiales difusas, la más frecuente y de peor pronóstico es la fibrosis pulmonar idiopática. Los tratamientos actuales son empíricos, con respuesta aleatoria, e incapaces de mejorar la supervivencia. Por este motivo la mayoría de los estudios básicos se han centrado en buscar respuestas sobre su fisiopatología y un abordaje terapéutico efectivo. El objetivo de esta revisión es dar a conocer los estudios experimentales que han empezado a abrir caminos hacia la comprensión del complejo proceso fibrótico.

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Cited by (19)

Autophagy modulation by irbesartan mitigates the pulmonary fibrotic alterations in bleomycin challenged rats: Comparative study with rapamycin
2022, Life Sciences
Citation Excerpt :
In the BLM and RAPA-treated group, RAPA (2.5 mg/kg/day; 2.5 ml/kg) was administered by gastric gavage for 14 days [28,29]. The rats' body weight was assessed before the experiment began on day 0, weekly during the study, and on day 28 of sacrificial cervical decapitation [32]. Individual lungs' wet and dry masses were quantified.
In pulmonary fibrosis, autophagy handles the maintenance of alveolar epithelial cells, prevents epithelial-mesenchymal transition (EMT), and controls collagen turnover. The mammalian target of rapamycin (mTOR) and its translational-dependent proteins are essential regulators of autophagy. Irbesartan (IRB) has earlier ameliorative effects in experimental pulmonary fibrosis. The current study aimed to explore therapeutic autophagy-modulated pulmonary fibrotic changes by IRB versus rapamycin (RAPA) in bleomycin (BLM)-challenged rats.
A single intratracheal BLM dose at day (0), IRB in different doses (10, 20, and 40 mg/kg) or RAPA (2.5 mg/kg) was given daily for 14 continuous days.
IRB significantly diminished the fibrotic lung scores. Pulmonary levels of transforming growth factor (TGF)-β1 and hydroxyproline exhibited marked attenuation in IRB (40 mg/kg)-treated rats compared to other treated groups. IRB (40 mg/kg) was not significantly different from RAPA. It downregulated the fibrotic lung phosphorylated mammalian target of rapamycin (p-mTOR) levels and augmented lung Unc-51-like autophagy activating kinase 1 (ULK1), LC3-I and LC3-II more than IRB (10 and 20 mg/kg)-treated fibrotic groups.
Autophagic effects via the mTOR signalling pathway may play a role in IRB's antifibrotic effects. Consideration of IRB as a therapeutic antifibrotic agent in pulmonary fibrosis needs further experimental and clinical long-term validation, especially in comorbid with primary hypertension, heart failure, and diabetic renal insults.
Bleomycin in the setting of lung fibrosis induction: From biological mechanisms to counteractions
2015, Pharmacological Research
Citation Excerpt :
The onset of fibrosis in this model can be biochemically and histologically observed by day 14, with a maximal response usually recorded around days 21–28. Unfortunately, in the murine model, lung impairment after intratracheal BLM is self-limiting, since the fibrosis resolves after 28 days of drug administration, and in C57Bl/6J mice lung function is recovered at about 6 weeks from the initial administration [27–29]. In brief, the use of experimental animal models allowed the identification of specific patterns and mechanisms of BLM-induced lung fibrosis, such as the characteristic patchy parenchymal inflammation, the reactive epithelial hyperplasia together with the epithelial–mesenchymal transition, the activation of fibroblasts to myofibroblasts, the formation of fibroblast foci, basement membrane damage, injury and apoptosis of alveolar epithelium, turnover and remodeling of extracellular matrix (ECM) components.
Bleomycin (BLM) is a drug used to treat different types of neoplasms. BLM's most severe adverse effect is lung toxicity, which induces remodeling of lung architecture and loss of pulmonary function, rapidly leading to death. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing lung fibrosis in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial–mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced lung fibrosis in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
Evaluation of the antifibrotic effect of fenofibrate and rosiglitazone on bleomycin-induced pulmonary fibrosis in rats
2012, European Journal of Pharmacology
Citation Excerpt :
Bleomycin instillation elicited an inflammatory phase and a fibrotic phase, and the “switch” between inflammation and fibrosis appears to occur around the ninth day after instillation. So, these changes in rats' body weights could be attributed to the development of severe inflammation in the early phase after bleomycin instillation (Molina et al., 2007; Moeller et al., 2008). Bleomycin instillation was accompanied by a significant accumulation of water in the lungs, as indicated by the fluid content (Genovese et al., 2005a; Oku et al., 2008).
Idiopathic pulmonary fibrosis is the most prevalent chronic fibrosing lung disease. Peroxisome proliferator-activated receptors-gamma agonists provide potential therapy for fibrotic diseases of the lung. Peroxisome proliferator-activated receptors-alpha agonists may be helpful in the treatment of lung inflammatory diseases, however their therapeutic potential on the “fibro-proliferative” process and extracellular matrix accumulation in idiopathic pulmonary fibrosis has been less well studied. So, the present study was conducted to evaluate the anti-fibrotic effects of fenofibrate (peroxisome proliferator-activated receptors-alpha agonist) alone and in combination with rosiglitazone (peroxisome proliferator-activated receptors-gamma agonist) on lung injury induced by bleomycin administration. Oral administration of either rosiglitazone (5 mg/kg/d) or fenofibrate (100 mg/kg/d) for 14 days, attenuated the severity of bleomycin-induced lung injury and fibrosis through decreasing lung water contents, lung fibrotic grading, lung hydroxyproline contents and lung transforming growth factor-beta1 levels; with no significant difference between them. Combined low doses of rosiglitazone (1 mg/kg/d) and fenofibrate (30 mg/kg/d) provided more benefits than full separate doses of each on the deleterious effects accompanied bleomycin administration.
These findings suggested the potential use of peroxisome proliferator-activated receptors-alpha ligands as anti-fibrotic agents in lung fibrosis. Additionally, the concurrent administration of fenofibrate and rosiglitazone in low doses has synergistic effect and enhanced the beneficial effects afforded by either fenofibrate or rosiglitazone.
In vivo and in vitro lung mechanics by forced oscillations: Effect of bleomycin challenge
2012, Respiratory Physiology and Neurobiology
Citation Excerpt :
Bleomycin challenge has been extensively used to study the pathophysiology of lung fibrosis and the relationship between changes in extracellular matrix components and biomechanical behavior of lung parenchyma (Dolhnikoff et al., 1999; Molina-Molina et al., 2007; Moeller et al., 2008; Pinart et al., 2009). Even though disease progression varies depending on the route of bleomycin administration (Scotton and Chambers, 2010), intratracheal instillation of bleomycin yields two distinct pathological phases: an early inflammatory phase, with alveolitis, interstitial edema and influx of inflammatory cells into lung parenchyma; and a late phase, characterized by myofibroblast proliferation, and deposition of matrix components (Bowden, 1984; Hay et al., 1991; Dolhnikoff et al., 1999; Molina-Molina et al., 2007; Pinart et al., 2009), resulting in pulmonary architecture distortion. Following bleomycin challenge, modifications in the oscillatory mechanics of lung tissue both in vivo and in vitro are caused by structural modifications of ECM (Dolhnikoff et al., 1999).
Bleomycin injury causes biomechanical changes secondary to inflammation, tissue remodeling and surfactant changes. We compared lung mechanics in open chest (OC) and tissue strip (TS) to better understand the pathophysiology of the alveolar interface between lung tissue and conducting airways. Thirty nine rats were studied at days 3, 7, and 15 after receiving saline or bleomycin (2.5 U kg⁻¹) intratracheally. Normalized elastance (E), hysteresivity (η) and exponent (β) of the power frequency dependence of elastance were determined in OC (lung parenchyma) and TS. Remodeling (hydroxyproline) and inflammation (myeloperoxidase and lung water) parameters were determined. E, η and β were higher in OC both in saline and bleomycin groups. The difference (OC-TS) of η and β correlated with myeloperoxidase and lung water but not with hydroxyproline. We concluded that differences between lung parenchyma and tissue mechanics are due to mechanical effects of inhomogeneities in saline animals. Changes at the alveolar interface after bleomycin are related to oxidative stress and extravascular lung water.
A phosphoinositide 3-kinase-γ inhibitor, AS605240 prevents bleomycin-induced pulmonary fibrosis in rats
2010, Biochemical and Biophysical Research Communications
Citation Excerpt :
Although bleomycin-induced pulmonary fibrosis model was doubted whether it well mimic IPF, it has been widely used in researches about pulmonary fibrosis in recent years. More researchers regard this animal model as a good one since it can be easily reproduced and it involves many aspects similar to IPF such as alveolitis in early stage of IPF [19]. Intratracheal administration of bleomycin induces acute alveolitis and interstitial inflammation, defined by the sequential recruitment of leukocytes [20].
Phosphoinositide 3-kinase-γ (PI3Kγ) has been identified to play the critical roles in inflammatory cells activation and recruitment in multiply inflammatory diseases and it promised to be a prospective target for relevant inflammatory diseases therapy. AS605240, a selective PI3Kγ inhibitor, has been proved effective on several inflammatory diseases. In this study, we investigated the protective effect of AS605240 on bleomycin-induced pulmonary fibrosis in rats. Our results showed that orally administration of AS605240 significantly prevented lung inflammation and reduced collagen deposition. AS605240 also inhibited augmented expression of TNF-α and IL-1β induced by bleomycin instillation. Moreover, the mRNA levels of TNF-α and IL-1β in lung were remarkably suppressed. Histological assessment found that AS605240 reduced the expression of TGF-β₁ and prevented T lymphocytes infiltration to lung. Phospho-Akt level in inflammatory cells by blocking PI3Kγ was down-regulated and the inhibition of Akt phosphorylation was further confirmed by Western blot. Our findings illustrated that AS605240 was effective for preventing pulmonary fibrosis by suppressing inflammatory cells recruitment and production of inflammatory cytokines. These findings also suggest that PI3Kγ may be a useful target in treating inflammation diseases and AS605240 may represent a promising novel agent for the future therapy of pulmonary fibrosis.
Liver Growth Factor Improves Pulmonary Fibrosis Secondary to Cadmium Administration in Mice
2010, Archivos de Bronconeumologia
El liver growth factor (LGF, ‘factor de crecimiento de hígado’) es un mitógeno con actividad regeneradora y antifibrótica con actividad incluso en localizaciones extrahepáticas. En este trabajo se administró LGF en un modelo de fibrosis pulmonar inducido con cloruro de cadmio (CdCl₂) para estudiar su capacidad antifibrótica.
Se instilaron 42 ratas Wistar macho con 0,5 ml/rata de CdCl₂ al 0,025% (n=21) o de salino (n=21). Transcurridos 35 días y una vez establecida la lesión se realizó el tratamiento con LGF y posteriormente el análisis de los parámetros funcionales —capacidad inspiratoria (CI), complianza pulmonar (CL), capacidad vital forzada (CVF) y flujo espiratorio forzado al 75% (FEF75%)—, morfometría —área interna alveolar y distancia media entre paredes alveolares— y contenido en colágeno y elastina.
La fibrosis pulmonar originada mediante CdCl₂ se caracterizó por un marcado descenso de la función pulmonar en comparación con los controles. Se redujó un 28% la CI, un 38% la CL, un 31% la CVF y un 54% la FEF75%, descenso que se revirtió parcialmente tras la inyección de LGF —el 18% en CI, el 27% en CL, el 19% en CVF y el 35% en FEF75%—. Además, se observó un incremento en la cantidad de colágeno y elastina del 165 y el 76%, respectivamente, en las ratas del grupo CdCl₂ frente a un 110 y un 34% tras la inyección de LGF.
Estos datos demuestran que el LGF mejora la función pulmonar y revierte parcialmente el incremento de las proteínas de matriz pulmonar producido por la instilación con CdCl₂.
Liver growth factor (LGF) is a liver mitogen with regenerating and anti-fibrotic activity even at extrahepatic sites. We used LGF in a lung fibrosis model induced by cadmium chloride (CdCl₂), to study its antifibrotic capacity.
Forty-two male Wistar rats were administered a single dose of 0.5 ml/rat of CdCl2 0.025% (n=21) or the same volume of saline (control group, n=21). After 35 days, once a lesion was established, we started a 3 week treatment with LGF, after which we determined lung function —inspiratory capacity (IC), lung compliance (LC), forced vital capacity (FVC) and expiratory flow at 75% (FEF75%)—, lung morphometry —alveolar internal area (AIA), mean linear intersection (LM)—, and collagen (both by Sirius red and hydroxyproline residues) and elastin contents.
Pulmonary fibrosis in CdCl₂ rats was characterized by a marked decrease in pulmonary function with respect to healthy controls —reductions of 28% in IC, 38% in CL, 31% in FVC, and 54% in FEF75%— which was partially recovered after LGF injection —18% IC, 27% CL, 19% FVC and 35% FEF75%—; increase in collagen and elastin contents —165% and 76%, respectively, in CdCl2 rats, versus 110% and 34% after LGF injection—; and increases in AIA and LM, partially reverted by LGF. Conclusions: Together, these data seem to demonstrate that LGF is able to improve lung function and partially reverts the increase in lung matrix proteins produced by CdCl₂ instillation.

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Review ArticleExperimental Models for the Study of Pulmonary Fibrosis: Current Usefulness and Future Promise

Arch Bronconeumol

Cell

Toxicology

Am J Pathol

Exp Mol Pathol

Biochem Biophys Res Commun

Am J Pathol

Am J Pathol

J Cell Physiol

Arch Bronconeumol

Chest

Am J Hum Genet

Chest

International multidisciplinary consensus classification of the idiopathic interstitial pneumonias

Am J Respir Crit Care Med

Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy

Ann Intern Med

Bleomycin-induced pulmonary in rats, biochemical demonstration of increased rate of collagen synthesis

Am Rev Respir Dis

Pulmonary fibrosis: searching for model answers

Am J Respir Cell Mol Biol

Changes in F-actin organization induced by hard metal particle exposure in rat pulmonary epithelial cells using laser scanning confocal microscopy

In Vitr Mol Toxicol

Bleomycin-induced interstitial pneumonia in dogs

Thorax

Changes in extracellular matrix and tissue viscoelasticity in bleomycin-induced lung fibrosis. Temporal aspects

Am J Respir Crit Care Med

Animal models of pulmonary fibrosis

Methods Mol Med

Evolution of three patterns of intra-alveolar fibrosis produced by bleomycin in rats

Pathol Int

Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis

Am J Pathol

Dual roles of IL-4 in lung injury and fibrosis

J Immunol

Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist

Am J Respir Crit Care Med

P-selectin upregulation in bleomycin induced lung injury in rats: effect of N-acetyl-L-cysteine

Thorax

Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin

Am J Respir Crit Care Med

Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis

Thorax

Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice

Hum Molt Genet

Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen

Am J Respir Cell Mol Biol

Bleomycin-induced apoptosis of alveolar epithelial cells requires angiotensin synthesis de novo

Am J Physiol Lung Cell Mol Physiol

Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis

J Clin Invest

High dose continuous infusion of bleomycin in mice: a new model for drug-induced pulmonary fibrosis. J

Pharmacol Exp Ther

Inhibition of amiodarone-induced lung fibrosis but not alveolitis by angiotensin system antagonists

Pharmacol Toxicol

Quantitative image analysis of drug-induced lung fibrosis using laser scanning confocal microscopy

Toxicol Sci

Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the hamster model of amiodarone-induced pulmonary toxicity

Toxicol Sci

Characterization of the effect of interleukin-10 on silica-induced lung fibrosis in mice

Am J Respir Cell Mol Biol

Pulmonary fibrogenesis after three consecutive inhalation exposures to chrysotile asbestos

Am J Respir Crit Care Med

Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis

J Exp Med

Inhalation delivery of manganese superoxide dismutaseplasmid/liposomes protects the murine lung from irradiation damage

Gene Ther

Proapoptotic Bid is required for pulmonary fibrosis

Proc Natl Acad Sci U S A

The perforin mediated apoptotic pathway in lung injury and fibrosis

J Clin Pathol

Review Article
Experimental Models for the Study of Pulmonary Fibrosis: Current Usefulness and Future Promise