| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
ABSTRACT |
|---|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Administration of bleomycin into the lungs of experimental animals has been utilized as a model to understand human pulmonary fibrosis. Most of the studies, however, have focused on early stages of the lung reaction. We hypothesized that chronic stages of the model may not mimic idiopathic pulmonary fibrosis, since in preliminary studies, lung volume and compliance were not decreased. Eight male Sprague-Dawley rats receiving intratracheal bleomycin (0.5 U/100 g body weight) underwent measurement of FRC, inspiratory capacity, and lung compliance 120 d later. Lung histologic changes were evaluated using light microscopy. Eight rats without intervention served as controls. Results show that our model, in early stages, has histologic changes no different from those previously described elsewhere. In chronic stages, however, the model does not behave as a restrictive syndrome: FRC is normal or increased, whereas lung compliance is normal. Focal peribronchiolar inflammation and fibrosis associated with paracicatricial emphysematous changes are the main histologic features of long-term lung remodeling after bleomycin. We conclude that while the chronic stages of the model may be informative in understanding mechanisms of fibrosis, care should be taken not to extrapolate to human idiopathic pulmonary fibrosis. We speculate that the model might resemble a particular subgroup of human interstitial lung disease, namely, those involving peribronchiolar structures.
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Bleomycin has been used largely as a chemotherapeutic agent because unlike other cytotoxic drugs, it does not induce major myelosuppression or immunosuppression. However, it exhibits a dose-dependent pulmonary toxicity, which has limited its clinical use (1).
This toxic effect of the drug has been utilized advantageously in a number of experimental approaches to pulmonary fibrosis in animal models. Several studies have reported that in the early stages of lung damage induced by bleomycin, the lesions are associated with biochemical and functional changes that resemble those of human pulmonary fibrosis, namely, inflammatory cell infiltration, increased collagen content, and reduced lung volumes and compliance (2).
As part of a long-term study to evaluate respiratory muscle function in the chronic stage of bleomycin-induced lung injury, we observed that changes in pulmonary function of animals surviving more than 3 mo after bleomycin administration were not compatible with a restrictive disorder.
This study was undertaken to test the hypothesis that the histologic pattern of bleomycin-induced lung damage in the chronic stages in the rat does not really mimic the particular histologic pattern of usual interstitial pneumonia (UIP), the pattern that defines idiopathic pulmonary fibrosis (IPF) in human beings (12). This hypothesis is consistent with a number of animal studies showing a reduction in histologic and biochemical markers of fibrosis in the bleomycin model with the use of antiinflammatory and antifibrotic agents (5, 13), whereas in humans IPF generally does not respond to treatment with these agents (21).
We performed physiologic studies in rats with bleomycin-induced lung damage 120 d after administration of a single dose of bleomycin intratracheally and evaluated the histologic changes in their lungs. Results showed that the late chronic phase of intratracheal bleomycin-induced lung damage in the rat neither physiologically behaves as a restrictive syndrome nor resembles the histologic pattern of UIP seen in humans. Focal peribronchiolar inflammation and fibrosis associated with pericicatricial emphysematous changes are the main histologic features of lung remodeling after long-term (120 d) bleomycin-induced pulmonary damage in the rat.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The study was performed in adult male Sprague-Dawley rats. Seventeen rats (pretreatment body weight, 250 to 280 g) received intratracheally a single dose of bleomycin (Nikableocina, Pharmacia & Upjohn, Kalamazoo, MI) 0.5 U/100 g body weight in 0.3 ml 0.15 M sterile NaCl. Bleomycin solution was prepared immediately before administration and was administered as a single dose directly into the trachea under light anesthesia with chloral hydrate (45 mg/100 g body weight) intraperitoneally. Via a small cervical skin incision and separation of the strap muscles, the trachea was exposed and punctured with a 25-gauge needle for the administration of bleomycin. After recovery from anesthesia, the animals were maintained in the animal care facility, with food and water ad libitum and with a 12-h dark/light cycle. Rats with no intervention (n = 9), maintained for the same period of time under similar conditions, served as controls. After a 4-mo period, animals were reanesthesized with chloral hydrate to study the mechanical properties of the respiratory system. After they were killed with an overdose of chloral hydrate, the histologic characteristics of the lungs were studied under light microscopy.
In addition, a group of animals receiving bleomycin were killed at 4 (n = 8), 7 (n = 8), 15 (n = 8), and 30 (n = 8) d to evaluate whether the initial histological changes were similar to those described in the literature at these intervals (1, 3, 5, 8).
For the study of the mechanical properties of the respiratory system in vivo, animals with 120-d postbleomycin instillation and their controls rested in the supine position inside a small animal whole-body pressure plethysmograph with a linear volume signal between 0.1 and 25 ml. Pressure changes in the plethysmograph were detected with a Statham PM 5 pressure transducer (Strathan Instruments, Hato Ray, Puerto Rico). Animals were tracheotomized via a cervical incision, a PE cannula (4 mm ID) was placed into the trachea, and a side port was connected to a Statham PM 23 DR 300 pressure transducer for the measurement of airway pressure. A water-filled polyethylene catheter with end and side holes was placed into the distal portion of the esophagus and connected to a Statham pressure transducer to measure esophageal pressure as an estimation of pleural pressure, and adjusted to maximize the measurement of esophageal pressure.
Transpulmonary pressure was calculated online by subtracting tracheal pressure from esophageal pressure. Changes in lung volume were calculated from changes in body box pressure. Airflow was calculated by electronic derivation. All variables were collected into a Biopac system (Biopac Systems, Santa Barbara, CA) at a speed of 30 samples per second. From the volume-time trace, the respiratory cycle was analyzed, and tidal volume (VT), inspiratory time (TI), TI/Ttot ratio, and mean inspiratory flow (VT/TI) were calculated.
After baseline evaluation and while still in the plethysmograph, lungs were inflated through the tracheal cannula to 25 cm H2O of transpulmonary pressure and allowed to passively deflate to end-expiratory lung volume (EELV). Inspiratory capacity (IC) was defined as the change in lung volume obtained by lung inflation from EELV to a transpulmonary pressure of 25 cm H2O.
At the conclusion of these physiologic measurements, the animals received intraperitoneally an overdose of chloral hydrate. In rapid succession, the animal abdomen was opened and the vena cava sectioned to allow for exsanguination. The animal's trachea was then occluded at EELV prior to the opening of the thoracic cage to allow for the removal of the trachea and heart-lung block. After the heart was removed, the volume of saline displaced by the lungs was measured. FRC was estimated by subtracting the lung's weight from this measured volume (assuming tissue density equal to 1).
Compliance of the lungs was measured in vitro after a volume history was obtained by sequentially inflating and deflating both lungs
cannulated at the level of the trachea. The lungs were gradually inflated with air in 1-ml steps up to a pressure of 20 to 25 cm H2O and
then gradually deflated. Two to three inflation-deflation cycles were
recorded for each animal. Pressure-volume data from the second or
third deflation curve was fitted to an exponential function of the form:
V=A
Be(
kP) , where V is the absolute lung volume in milliliters,
P is pressure in cm H2O, and A, B and k (cm H2O1) are constants
(22). The exponent k, an index of compliance that describes the nonlinear behavior of the lung, was calculated. The best-fit exponential
function was obtained by an iterative least-squares method using
Graph Pad Prism (GraphPad Software, Inc., San Diego, CA).
Histologic Evaluation
Lung fixation was obtained by filling the lungs through the tracheal cannula to 25 cm H2O with 10% neutral buffered formaldehyde solution. The trachea was then occluded and fixation allowed to continue for 4 to 10 d prior to the study. Parasagittal sections of the right lung were embedded in paraffin. Five 5-µm sections were stained with hematoxylin-eosin and examined by light microscopy at magnifications ×40 and ×100. A score was developed to analyze the histologic changes (Table 1). The pathologist was blinded with regard to both the condition of the lung (control versus experimental) and the time course of the changes.
|
Statistical Analysis
Mann-Whitney U test, ANOVA, and the Tukey post-hoc test were used for comparisons. Results are expressed as means ± 1 SD. A p value < 0.05 was considered statistically significant (23).
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The changes in body weight and respiratory function indices for the group of animals with chronic lung damage are shown in Table 2.
|
Nine of 17 animals died before completing the predetermined time of death of the chronic group, yielding a mortality rate of 55%. Most animals died in the first week after treatment. The changes in body weight after bleomycin in the animals that survived are shown in Figure 1. Most animals decreased body weight in the first 15 d after treatment and later recovered, without reaching the final body weight of the control animals.
|
Lung volume data are shown in Figure 2 for the control and treatment groups. On average, FRC was larger in the bleomycin-treated animals than in the control animals (7.44 ± 1.37 versus 5.47 ± 2.3), but the difference did not reach statistical significance (p < 0.08). Inspiratory capacity was significantly lower in the animals treated with bleomycin than in the control series (p < 0.05).
|
In vitro lung compliance was not different from compliance
in control animals, since the exponent k was 0.140 ± 0.03 cm
H2O1 in control animals and 0.138 ± 0.03 in experimental animals (Table 2). However, a significant positive correlation
was found between FRC and the value of the exponent k (r = 0.87, p < 0.02) in the group of animals with 120 d after bleomycin. The animals with the largest FRC were those with the
largest increase in lung compliance.
Histologic Assessment of Acute and Subacute Lung Injury
The histologic pattern of acute and subacute lung injury (
30 d) in our model was not different from what has been published elsewhere with similar doses of intratracheal bleomycin
in rats and hamsters (1, 3, 5, 8). The initial acute lung injury
was focal around the bronchiole, but by Day 7 it became widespread, with coalescence of areas of involved lung parenchyma. These areas showed edematous changes, hyaline membranes,
aggregation of polymorphonuclear neutrophils in both alveoli
and interstitium, and enlarged hyperplastic type II alveolar
cells. These histologic findings are compatible with the acute
phase of diffuse alveolar damage (DAD) in humans. Lung sections from a control rat and from rats killed 4 and 7 d after bleomycin administration are shown in Figure 3.
|
By 15 d after bleomycin, the areas of inflammation were less coalescent, there was collagen deposition, and the peribronchiolar nature of the reaction was evident. Epithelial-lined cystic spaces were present in peribronchiolar areas and contained round cells (Figure 4). In some animals, intraluminal pseudopolyps like those described in bronchiolitis obliterans were seen. These pseudopolyps were not seen at any other stage.
|
Examination on Day 30 (Figure 5) showed mild peribronchiolar fibrosis in association with inflammatory cell infiltration. No fibrosis was seen in areas without inflammation.
|
Histopathologic features in the lungs of animals killed at 120 d after bleomycin are seen in Figures 6 and 7. Bronchiolar and peribronchiolar fibrosis and inflammation persisted, together with large areas of intervening normal lung. Peribronchiolar emphysematous changes consisting of fragmentation of alveolar septa and enlargement of alveolar spaces were found in all cases at this stage.
|
|
The time course of the inflammatory changes in the lungs of the bleomycin-treated animals is illustrated in Figure 8. Diffuse interstitial and alveolar inflammation are present in the early stages of the process and decrease with time. Peribronchiolar inflammation persists for the entire time of the study.
|
The scores for fibrosis (solid bars) and for emphysema (hatched bars) are shown in Figure 9. The fibrosis score represents an average of the diffuse and focal distribution of fibrosis. Emphysema score takes into account both enlargement of alveolar spaces and fragmentation of alveolar septa. Emphysema score was significantly increased at early stages (15 and 30 d) after bleomycin administration, and further increased by 120 d postbleomycin.
|
To evaluate in which way the enlargement of air spaces component was influencing the emphysema score, we also analyzed the score for fragmentation of alveolar septa alone, finding a similar profile as that shown in Figure 9, which combines both fragmentation of the alveolar septa and air-space enlargement.
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The pulmonary reaction that follows administration of intratracheal bleomycin in experimental animals has been extensively used as a model of human pulmonary fibrosis. Most of the studies, however, have focused on the early stages of the lung reaction. The data presented in this report indicate that the early stages of intratracheal bleomycin-induced lung injury in the rat has some histologic similarities to DAD, whereas the more chronic stages of the disease exhibit a bronchiolocentric distribution of the lesions with development of peribronchiolar paracicatricial emphysema and a nonrestrictive functional pattern in physiologic studies. Four months after intratracheal administration of a single dose of bleomycin, the early widespread patchy lung injury induced by the drug resolves leaving focal inflammation and interstitial fibrosis. At this chronic stage interstitial and alveolar fibrosis are restricted to the peribronchiolar areas in which predominantly mononuclear inflammation persists accompanied by focal paracicatricial emphysema. Physiologic data are consistent with the histologic changes: instead of the reduction in lung volume and compliance typically seen in the early stages of bleomycin-induced lung injury, FRC becomes normal or increased and lung compliance normalizes.
The histologic characteristics of the initial lung injury in our study (4 to 30 d postbleomycin) are not different from what has been published elsewhere with similar doses of intratracheal bleomycin (1, 3, 5, 8). Most investigators use between 0.5 and 1 U of intratracheal bleomycin per 100 g of body weight, since larger doses greatly increase mortality. The effect of the dose used by us on survival and on body weight is also comparable to previous studies.
Initial histologic changes consist of interstitial and intraalveolar edema with varying amounts of hemorrhage, fibrin deposition, and hyaline membranes, compatible with DAD. The time course of the histologic changes in the early stages after bleomycin administration is also compatible with DAD. Although the patchy distribution of the lesions is a common denominator in several studies using intratracheal bleomycin, the bronchiolocentric nature of the lesion has not been stressed in most of the studies. Probably what makes it difficult to reveal the bronchiole as the center of the lesion is the coalescence of areas of involved lung parenchyma in the early stages. Our study, by focusing on the more chronic stages of the bleomycin model permitted a better demonstration of the bronchiolocentric nature of the initial injury. In the chronic phase, bronchiolar involvement consists of inflammation and varying degrees of fibrosis of the airway wall and of the peribronchiolar spaces. It is not of the bronchiolitis obliterans type, since no intraluminal pseudopolyps were seen.
Repeated intravenous or intraperitoneal doses of bleomycin, as well as single and repeated intratracheal doses of the drug have been used in a number of studies on the effects of bleomycin on the lung of experimental animals. Whether administered subcutaneously, intraperitoneally, intravenously, or intratracheally, bleomycin is known to induce a dose-dependent pneumonitis that heals with fibrosis (1, 6, 24). However, the route of bleomycin administration determines important differences in the distribution of the lesions. The histologic pattern of bleomycin-induced lung damage after intravenous or intraperitoneal administration is not bronchiolocentric; instead, the initial site of injury is the endothelium of capillaries and larger vessels and the perivascular lung structures of the subpleural parenchyma (24).
Katzenstein and Myers (21) proposed a novel classification of the idiopathic interstitial pneumonias in humans. The entities in this classification, although sharing many features, are pathologically distinct and differ clinically with regard to presentation, course, and response to therapy. Temporal heterogeneity revealed by a marked variation from field to field both in the degree of lung involvement and in the nature and appearance of the interstitial infiltrate is required for the diagnosis of UIP, the most common of the idiopathic interstitial pneumonias (21). Progressive restrictive defects in pulmonary function are generally demonstrated in UIP. Intratracheal bleomycin-induced chronic lung reaction does not fulfill the requirements for the histologic diagnosis of UIP, since temporal heterogeneity is not present. The process at low magnification typically shows uniform peribronchiolar inflammation and fibrosis with scar emphysema next to large areas of intervening normal lung with no collagen deposition. In addition, the functional abnormalities are not of the restrictive type. It is possible to speculate that this difference is due to the fact that with the bleomycin model, lung injury occurrs once, whereas in UIP the lung at a given time probably reflects the effect of repetitive bouts of acute lung injury over many years. Studies with repeated doses of intratracheal bleomycin could be of help to elucidate if an UIP pattern is possible after repeated bouts of lung injury induced by the drug. Although we are not aware of any study evaluating the presence of temporal heterogeneity in models of chronic lung injury induced by bleomycin, the study by Zia and colleagues (4) in hamsters receiving small repeated intratracheal doses of bleomycin, shows focal peribronchovascular distribution of the lesions. This finding, if associated to a nonrestrictive defect in lung mechanics, would make the bleomycin chronic model less likely to represent a model of UIP.
Because little is known about the cellular processes involved in the response to therapy in fibrotic lung diseases in humans, the bleomycin animal model has been used as a method to investigate pharmacologic approaches to the treatment of human pulmonary fibrosis. A number of drugs have been tested and found capable of modifying the time course of bleomycin-induced lung damage in animal models (13). However, most of these drugs do not modify the course of most cases of human UIP (25). The results of our study could help to understand this discrepancy, since the histopathologic pattern of bleomycin-induced chronic damage does not really mimic UIP.
The chronic stage of the single dose bleomycin model does not even resemble the histologic changes seen in patients receiving bleomycin as treatment (1, 26). Bleomycin therapy induces DAD with a high lethality rate and progressive diffuse lung fibrosis in most patients who survive, despite suppression of the drug.
We found that changes in the chronic stages of the intratracheal bleomycin model, if anything, resemble more those described in studies of human COPD (27), in which mural inflammation and fibrosis at the level of the bronchioles is associated with emphysematous changes.
Pericicatricial emphysematous lesions surrounding the bronchioles have not been reported in the early stages after bleomycin administration. In the study of Snider and colleagues in hamsters (3), some foci of paracicatricial emphysema with alveolar distention and dilatation were described in the lungs 90 to 180 d after intratracheal bleomycin, but no interpretation was offered. In this regard, we speculate that fragmentation of the alveolar septa and the enlargement of the peribronchiolar air spaces could be secondary to proteolitic destruction of lung parenchyma in the early stages of the bleomycin-induced injury and that these changes become apparent only after DAD resolves. Support for this hypothesis can be found in our own results showing that the emphysema score is increased in early stages (15 and 30 d) after bleomycin administration (Figure 9). Additional support is found in the study by Koslowski and colleagues (28) who measured the activity of several proteinases during the development of bleomycin-induced pulmonary fibrosis in rats and found a 10-fold increase in the early inflammatory period. Interestingly, they also found that during the period of chronic inflammation, the activities of several cathepsins remained increased. Another hypothesis for the emphysematous changes could be that centrilobular emphysema is secondary to the bronchiolar damage.
The findings of our study provides morphologic and physiologic data not yet available about the late stages of bleomycin-induced lung injury, since most of the studies in the literature have focused on early stages of the lung reaction. Our results have several relevant implications. First, as with any result from animal models of human diseases, extrapolation to the situation in humans needs to be done with caution. Special care is needed to extrapolate data from the more chronic stages of the intratracheal bleomycin model to human pulmonary fibrosis in general, as it has been the case until now. The model resembles only a particular group of interstitial lung diseases in humans, mainly those associated with peribronchovascular involvement, which in general have a better response to treatment. Second, the changes we have described gives some insight into the problem of the discrepancy between the favorable response of bleomycin-induced lung injury to antiinflammatory and antifibrotic agents and the lack of response to drugs in human IPF. Third, the design of long term protocols with the aim of modifying the time course of the changes in the animal model should take into consideration the long term functional and morphologic natural evolution of the model.
| |
Footnotes |
|---|
Correspondence and requests for reprints should be addressed to Gisella Borzone, MD, PhD, Marcoleta 345, piso 4, Santiago, Chile. Email: gborzone{at}med.puc.cl
(Received in original form June 26, 2000 and in revised form August 13, 2000).
Acknowledgments:
Supported by Grants 195 1197 and 198 0917 from Fondo Nacíonal de Ciencia
Tecnología de Chile.
| |
References |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1. Cooper JA, White D, Matthay R. Drug-induced pulmonary disease. Am Rev Respir Dis 1986; 133: 321-340 [Medline].
2. Snider GL, Celli BR, Goldstein RH, O'Brien JJ, Luey EC. Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Am Rev Respir Dis 1978; 117: 289-297 [Medline].
3. Snider GL, Hayes JA, Korthy AL. Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin: pathology and stereology. Am Rev Respir Dis 1978; 117: 1099-1108 [Medline].
4. Zia S, Hyde DM, Giri SN. Development of a bleomycin hamster model of subchronic lung fibrosis. Pathology 1992; 24: 155-163 [Medline].
5. Thrall RS, McCormick JR, Jack RM, McReynolds RA, Ward PA. Bleomycin-induced pulmonary fibrosis in the rat: inhibition with indomethacin. Am J Pathol 1979; 95: 117-127 [Abstract].
6. Aso Y, Toneda K, Kikkawa Y. Morphologic and biochemical study of pulmonary changes induced by bleomycin in mice. Lab Invest 1976; 35: 558-568 [Medline].
7.
Osanai K,
Takahashi K,
Sato S,
Iwabuchi K,
Ohtake K,
Sata M,
Yasui S.
Changes of lung surfactant and pressure-volume curve in bleomycin-induced pulmonary fibrosis.
J Appl Physiol
1991;
70:
1300-1308
8. Usuki J, Fukuda Y. Evolution of three patterns of intra-alveolar fibrosis produced by bleomycin in rats. Pathol Int 1995; 45: 552-564 [Medline].
9. Thrall RS, Swendsen CL, Shannon T, Kennedy CA, Frederick DS, Grunze MF, Sulavik SB. Correlation of changes in pulmonary surfactant phospholipids with compliance in bleomycin-induced pulmonary fibrosis in the rat. Am Rev Respir Dis 1987; 136: 113-118 [Medline].
10. Chandler DB, Hyde DM, Giri SN. Morphometric estimates of infiltrative cellular changes during the development of bleomycin-induced pulmonary fibrosis in hamsters. Am J Pathol 1983; 112: 170-177 [Abstract].
11. Bowden DH. Unraveling pulmonary fibrosis: the bleomycin model. Lab Invest 1984; 50: 487-488 [Medline].
12. Leslie KO. The pathology of idiopathic pulmonary fibrosis. In: King TE, Jr, editor. ATS continuing education monograph series: new approaches to managing idiopathic pulmonary fibrosis. 8-13. New York: American Thoracic Society; 2000.
13. Phan SH, Thrall RS, Williams C. Bleomycin-induced pulmonary fibrosis: effects of steroids on lung collagen metabolism. Am Rev Respir Dis 1981; 124: 428-434 [Medline].
14.
Azuma A,
Furuta T,
Enomoto T,
Hashimoto Y,
Uematsu K,
Nukariya N,
Murata A,
Kudoh S.
Preventive effect of erythromycin on experimental bleomycin-induced acute lung injury in rats.
Thorax
1998;
53:
186-189
15. Iyer SN, Margolin SB, Hyde DM, Giri SN. Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model. Exp Lung Res 1998; 24: 119-132 [Medline].
16. Piguet PF, Van GY, Gui J. Heparin attenuates bleomycin but not silica-induced pulmonary fibrosis in mice: possible relationship with involvement of myofibroblasts in bleomycin, and fibroblasts in silica-induced fibrosis. Int J Exp Pathol 1996;77:155-161.
17. Dussaubat N, Capetillo M, Orfali J, Rocco V, Lathrop ME, Mendoza R, Oyarzún M. Inhibitory effect of cyclosporin A and prednisone on bleomycin-induced pulmonary fibrosis in the rat. Rev Chil Enf Respir 1997; 13: 93-101 .
18. Chandler DB, Fulmer JD. The effect of deferoxamine on bleomycin- induced lung fibrosis in the hamster. Am Rev Respir Dis 1985; 131: 596-598 [Medline].
19. Oyarzun MJ, Dussaubat N, Capetillo M, Rocco V, Mendoza R, Lathrop ME. Pharmacological inhibition of bleomycin-induced pulmonary fibrosis in the rat. Eur Respir J 1995; 8: 544s .
20.
Zuckerman JE,
Hollinger MA,
Giri SN.
Evaluation of antifibrotic drugs
in bleomycin-induced pulmonary fibrosis in hamsters.
J Pharmacol
Exp Ther
1980;
213:
425-431
21.
Katzenstein ALA,
Myers JL.
Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification.
Am J Respir Crit Care Med
1998;
157:
1301-1315
22.
Colebatch H,
Ng CK,
Nikov N.
Use of an exponential function for elastic recoil.
J Appl Physiol
1979;
46:
387-393
23. Sokal RR, Rohif FJ, editors. Biometry. New York: Freeman and Co.; 1981.
24. Jones AW, Reeve NL. Ultrastructural study of bleomycin-induced pulmonary changes in mice. J Pathol 1978; 14: 227-233 .
25. International Consensus Statement. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med 2000;161:646-664.
26. Myers JL. Pathology of drug-induced lung disease. In: Katzenstein ALA, editor. Surgical pathology of non-neoplastic lung disease. Philadelphia, Saunders; 1997.
27. Niewoehner DE, Cosio MG. Chronic obstructive lung disease: the role of airway disease, with special emphasis on the pathology of small airways. In: Thurlbeck WM, Abell MR, editors. The lung. Baltimore: Williams & Wilkins Company; 1979.
28. Koslowski R, Knoch KP, Wenzel KW. Proteinases and proteinase inhibitors during the development of pulmonary fibrosis in rat. Clin Chim Acta 1998; 271: 45-46 [Medline].
This article has been cited by other articles:
 |
|
 |
|
  T J Williams and J W Wilson Challenges in pulmonary fibrosis: 7 {middle dot} Novel therapies and lung transplantation Thorax, March 1, 2008; 63(3): 277 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Gauldie and M. Kolb Animal models of pulmonary fibrosis: how far from effective reality? Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L151 - L151. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Borzone, L. Liberona, P. Olmos, C. Saez, M. Meneses, T. Reyes, R. Moreno, and C. Lisboa Rat and hamster species differences in susceptibility to elastase-induced pulmonary emphysema relate to differences in elastase inhibitory capacity Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1342 - R1349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vittal, H. Zhang, M. K. Han, B. B. Moore, J. C. Horowitz, and V. J. Thannickal Effects of the Protein Kinase Inhibitor, Imatinib Mesylate, on Epithelial/Mesenchymal Phenotypes: Implications for Treatment of Fibrotic Diseases J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 35 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Gonzalez, F. Le Bellego, and M. S. Ludwig Imbalance of Receptor-Regulated and Inhibitory Smads in Lung Fibroblasts from Bleomycin-Exposed Rats Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 206 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Nakagome, M Dohi, K Okunishi, R Tanaka, J Miyazaki, and K Yamamoto In vivo IL-10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF-{beta} in the lung Thorax, October 1, 2006; 61(10): 886 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Kelly, R. Leigh, S. E. Gilpin, E. Cheng, G. E. M. Martin, K. Radford, G. Cox, and J. Gauldie Cell-specific Gene Expression in Patients with Usual Interstitial Pneumonia Am. J. Respir. Crit. Care Med., September 1, 2006; 174(5): 557 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsuchida, D. Engelberts, V. Peltekova, N. Hopkins, H. Frndova, P. Babyn, C. McKerlie, M. Post, P. McLoughlin, and B. P. Kavanagh Atelectasis Causes Alveolar Injury in Nonatelectatic Lung Regions Am. J. Respir. Crit. Care Med., August 1, 2006; 174(3): 279 - 289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Chua and G. J. Laurent Neutrophil elastase: mediator of extracellular matrix destruction and accumulation. Proceedings of the ATS, July 1, 2006; 3(5): 424 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Agostini and C. Gurrieri Chemokine/Cytokine cocktail in idiopathic pulmonary fibrosis. Proceedings of the ATS, January 1, 2006; 3(4): 357 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Chua, J. Gauldie, and G. J. Laurent Pulmonary Fibrosis: Searching for Model Answers Am. J. Respir. Cell Mol. Biol., July 1, 2005; 33(1): 9 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vittal, J. C. Horowitz, B. B. Moore, H. Zhang, F. J. Martinez, G. B. Toews, T. J. Standiford, and V. J. Thannickal Modulation of Prosurvival Signaling in Fibroblasts by a Protein Kinase Inhibitor Protects against Fibrotic Tissue Injury Am. J. Pathol., February 1, 2005; 166(2): 367 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Cosgrove, K. K. Brown, W. P. Schiemann, A. E. Serls, J. E. Parr, M. W. Geraci, M. I. Schwarz, C. D. Cool, and G. S. Worthen Pigment Epithelium-derived Factor in Idiopathic Pulmonary Fibrosis: A Role in Aberrant Angiogenesis Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 242 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Williams, D. Malarkey, L. Cohn, D. Patrick, J. Dye, and G. Toews Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Morphology and Ultrastructural Evidence for a Type II Pneumocyte Defect Chest, June 1, 2004; 125(6): 2278 - 2288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Berman, D. Serlin, X. Li, G. Whitley, J. Hayes, D. C. Rishikof, D. A. Ricupero, L. Liaw, M. Goetschkes, and A. W. O'Regan Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1311 - L1318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mata, A. Ruiz, M. Cerda, M. Martinez-Losa, J. Cortijo, F. Santangelo, A. Serrano-Mollar, A. Llombart-Bosch, and E.J. Morcillo Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats Eur. Respir. J., December 1, 2003; 22(6): 900 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Koslowski, K. Knoch, E. Kuhlisch, D. Seidel, and M. Kasper Cathepsins in bleomycin-induced lung injury in rat Eur. Respir. J., September 1, 2003; 22(3): 427 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Aoshiba, T. Tsuji, and A. Nagai Bleomycin induces cellular senescence in alveolar epithelial cells Eur. Respir. J., September 1, 2003; 22(3): 436 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Suzuki, K. Aoshiba, N. Yokohori, and A. Nagai Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition Augments a Murine Model of Pulmonary Fibrosis Cancer Res., August 15, 2003; 63(16): 5054 - 5059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bergeron, P. Soler, M. Kambouchner, P. Loiseau, B. Milleron, D. Valeyre, A.J. Hance, and A. Tazi Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-{beta} and IL-10 Eur. Respir. J., July 1, 2003; 22(1): 69 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Suga, Y. Yuan, N. Ogasawara, T. Tsukuda, and N. Matsunaga Altered Clearance of Gadolinium Diethylenetriaminepentaacetic Acid Aerosol from Bleomycin-injured Dog Lungs: Initial Observations Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1704 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Duggan, C. L. McCaul, P. J. McNamara, D. Engelberts, C. Ackerley, and B. P. Kavanagh Atelectasis Causes Vascular Leak and Lethal Right Ventricular Failure in Uninjured Rat Lungs Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1633 - 1640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Betsuyaku, K. Kadomatsu, G. L. Griffin, T. Muramatsu, and R. M. Senior Increased Basigin in Bleomycin-Induced Lung Injury Am. J. Respir. Cell Mol. Biol., May 1, 2003; 28(5): 600 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Atkinson and R. M. Senior Matrix Metalloproteinase-9 in Lung Remodeling Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 12 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ghosh, T. Mendoza, L. A. Ortiz, G. W. Hoyle, C. D. Fermin, A. R. Brody, M. Friedman, and G. F. Morris Bleomycin Sensitivity of Mice Expressing Dominant-Negative p53 in the Lung Epithelium Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 890 - 897. [Abstract] [Full Text]
|
|
|
|
|
|
E. C. Gabazza, O. Taguchi, Y. Adachi, E. C. Gabazza, O. Taguchi, and Y. Adachi BLEOMYCIN-INDUCED LUNG FIBROSIS: THE AUTHORS SHOULD HAVE USED ANOTHER METHOD TO INDUCE PULMONARY LESIONS RESEMBLING HUMAN IDIOPATHIC PULMONARY FIBROSIS Am. J. Respir. Crit. Care Med., March 15, 2002; 165(6): 845b - 846. [Full Text]
|
|
|
|
|
|
M. J. TOBIN Tuberculosis, Lung Infections, Interstitial Lung Disease, and Socioeconomic Issues in AJ |