BLEOMYCIN-INDUCED LUNG FIBROSIS: THE AUTHORS SHOULD HAVE USED ANOTHER METHOD TO INDUCE PULMONARY LESIONS RESEMBLING HUMAN IDIOPATHIC PULMONARY FIBROSIS

To the Editor :

We have read with much interest the recent article by Borzone and colleagues that found that bleomycin (BLM)-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis (IPF) (1). We believe that there is a model of BLM-induced lung fibrosis that more closely resembles the pathological and functional changes observed in human IPF. Borzone and colleagues induced lung fibrosis by intratracheally administering a single dose of BLM to rats. They found that very soon (on Day 15) after BLM instillation, there are peribronchiolar inflammation with mild coalescent areas of lung parenchyma, and that on Day 120, there are only uniform areas of mild peribronchiolar fibrosis with areas of normal lung or emphysema, together with a normal pulmonary functional test. Obviously, the lack of both restrictive pattern and temporal heterogeneity of the pulmonary lesions are against the diagnosis of usual interstitial pneumonitis (UIP), the most common form of IPF (2). The major flaw in this study is the lack of a control group of animals receiving repeated doses of BLM. A single dose of BLM may be insufficient for inducing IPF, because this disease is believed to be the result of repeated bouts of lung injury.

Harrison and Lazo previously reported a method that produces pulmonary lesions different from those induced by the classical intratracheal procedure in terms of intensity and time course of the lesions (3). They induced lung fibrosis by continuously administering BLM through an osmotic minipump placed subcutaneously. This technique allows the induction of pronounced pulmonary inflammation and fibrosis, with lesions mainly localized in the subpleural parenchyma, and to a degree far greater than that induced by the single intratracheal BLM instillation. We have also found that by using this method, heterogeneous and nonuniform areas of inflammation and fibrosis occur in the lung, thereby resembling the UIP pattern recently described by Katzeintein (2, 4). Persistent deposition of collagen with restrictive pattern of lung function (our unpublished observation) even five to six weeks after BLM exposure supports the progressive nature of the pulmonary lesion in this model. We were really surprised that Borzone and colleagues did not include a group of animals using this method, and that they did not even mention it in their discussion as an alternative approach.

Another important flaw in the study by Borzone and colleagues is the lack of follow-up of the lung functional parameters. BLM-induced lung disease in patients is associated with progressive loss of lung function, despite cessation of cytotoxic therapy (5). Borzone and colleagues measured lung functional parameters only on Day 120 after BLM instillation; they presented no data on lung function at the early phases of BLM-induced lung injury. Early evaluation of lung function is necessary to discriminate whether restrictive lung was absent from the beginning of lung injury, or whether it was just a temporary change that reverses over time. In summary, we believe that it is still too premature to draw the general conclusion that "bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis," because different methods of BLM administration may induce different types of pulmonary lesions. Rather, the conclusion of Borzone and colleagues should be that "a single intratracheal dose of bleomycin induces chronic lung damage that does not resemble human idiopathic pulmonary fibrosis."

Mie University School of Medicine, Tsu City, Mie Prefecture, Japan

1. Borzone G, Moreno R, Urrea R, Meneses M, Oyarzún M, Lisboa C. Bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001; 163: 1648-1653 [Abstract/Free Full Text].

2. Katzenstein AA, Myers JL. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157: 1301-1315 [Free Full Text].

3. Harrison JH, Lazo JS. High dose continuous infusion of bleomycin in mice: a new model for drug-induced pulmonary fibrosis. J Pharmacol Exp Ther 1987; 243: 1185-1194 [Abstract/Free Full Text].

4. Yasui H, Gabazza EC, Tamaki S, Kobayashi T, Hataji O, Yuda H, Shimizu S, Suzuki K, Adachi Y, Taguchi O. Intratracheal administration of activated protein C inhibits bleomycin-induced lung fibrosis in the mouse. Am J Respir Crit Care Med 2001; 163: 1660-1668 [Abstract/Free Full Text].

5. Myers JL. Pathology of drug-induced lung disease. In: Katzenstein and Askin's surgical pathology of non-neoplastic lung disease, 3rd ed. Tokyo: W. B. Saunders; 1997. p. 81-111.

From the Authors:

We thank Drs. Gabazza, Taguchi, and Adachi for their interest in our research (1). As stated in our introduction, the study originated as part of a long-term study to evaluate respiratory muscle function in the chronic stages of intratracheal bleomycin-induced lung injury and did not intend to compare different methods for inducing lung fibrosis. We first observed that changes in pulmonary function of animals surviving more than three months after a single dose of intratracheal bleomycin were not compatible with a restrictive disorder. Furthermore, we found that focal peribronchiolar inflammation and fibrosis associated with pericicatricial emphysematous changes were the main histologic features, revealing that the model does not resemble idiopathic pulmonary fibrosis.

As mentioned in our discussion, the route of bleomycin administration determines important differences in distribution of the lesions: after intravenous or intraperitoneal administration, the histologic pattern 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 (2). It remains to be studied if bleomycin administered via a nontracheal route is capable of inducing the usual interstitial pneumonitis pattern (heterogeneity of the lesions).

Since the administration of a single intratracheal dose of bleomycin is the most frequently used method for inducing pulmonary fibrosis in experimental animals, the communication of our findings with this method seemed highly relevant. As a matter of fact, a Medline search of the last five years (1997-2001) showed that among 100 articles on pulmonary fibrosis induced by bleomycin having the method of administration explicited in the abstract, 83% used the single intratracheal dose of bleomycin and 17% used either repeated intratracheal doses or other routes of bleomycin administration. Although the method of Harrison and Lazo (3) for inducing lung fibrosis was described in 1987, it has rarely been used, and more studies are needed to really demonstrate that it is a model of UIP.

We did not present data on lung function in early phases of bleomycin- induced lung injury because the histologic pattern of acute and subacute lung injury was not different from what has been described by others (4, 5) showing significant restrictive defects (6).

Drs. Gabazza and colleagues are right in that the conclusions of our article apply only to the single intratracheal dose of bleomycin model, still the most frequently used method for inducing pulmonary fibrosis.

Pontificia Universidad Católica de Chile, Santiago, Chile

Manuel Meneses, and Manuel Oyarzún

Universidad de Chile, Santiago, Chile

1. Borzone G, Moreno R, Urrea R, Meneses M, Oyarzún M, Lisboa C. Bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001; 163: 1648-1653 .

2. Jones AW, Reeve NL. Ultrastructural study of bleomycin-induced pulmonary changes in mice. J Pathol 1978; 14: 227-233 .

3. Harrison JH, Lazo JS. High dose continuous infusion of bleomycin in mice: a new model for drug-induced pulmonary fibrosis. J Pharmacol Exp Ther 1987; 243: 1185-1194 .

4. 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].

5. Dussaubat N, Capetillo M, Lathrop ME, Mendoza R, Oyarzún M. The effects of imidazole on pulmonary damage induced by bleomycin. Biol Res 1995; 28: 261-266 [Medline].

6. Snider GL, Celli B, Goldstein R, O'Brien J, Lucey E. Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin: lung volumes, volume-pressure relations, carbon monoxide uptake, and arterial blood gas studies. Am Rev Respir Dis 1978; 117: 289-297 [Medline].