Abstract
AbstrqactThe single intratracheal instillation (ITI) of bleomycin (BLM) is a widely used method for inducing experimental pulmonary fibrosis in rat model. In the present study, pulmonary function tests (PFTs) of tidal volume (VT), minute volume (VM), and respiratory frequency (FR) have been applied to study their possibility as a tool to monitor the progress of BLM-induced lung injury in rat model. Rats were treated with a single ITI of BLM (2.5 mg/kg) or saline (control). Animals were euthanized at 3, 7, 14, 21, and 28 days post-ITI. Lung toxicity effects were evaluated by inflammatory cell count, lactate dehydrogenase (LDH) activity in the bronchoalveolar lavage fluid (BALF), and light microscopic examination of lung injury. The PFT parameters were measured immediately before the animals were sacrificed. BLM treatment induced significant cellular changes in BALF-increase in number of total cells, neutrophils, and lymphocytes along with sustained increase in number of macrophages compared to the controls at days 3, 7, and 14. BALF LDH level was significantly increased compared to that in the controls up to day 14. On day 3, infiltration of neutrophils was observed in the alveolar spaces. These changes developed into marked peribronchiolar and interstitial infiltration by inflammatory cells, and extensive thickening of the interalveolar septa on day 7. At 14, 21, and 28 days, mild peribronchiolar fibrosis was observed along with inflammatory cell infiltration. The results of PFT show significant consistencies compared to the results of other toxicity tests. These data demonstrate that the most suitable time point for assessing lung fibrosis in this model is 14 days post-ITI of BLM based on the observation of fibrosis at 14, 21, and 28 days. Further, the progress of lung injury can be traced by monitoring the PFT parameters of FR, VT, and VM.
Highlights
Idiopathic pulmonary fibrosis (IPF) is characterized by lung inflammation and abnormal tissue repair brought about by cytokines and interactions between several cell types, resulting in the expression of collagen gene and subsequent collagen deposition in the lungs (Piguet et a/., 1990; Gross and Hunninghake, 2001; GharaeeKermani and Phan, 2005)
Recovery rates of bronchoalveolar lavage fluid (BALF) ranged from 95% to 100% and were not
The reason is that the severity of induced disease models with the same dose of 8LM applied in this study (2.5 mg/kg, 8.W.) may be different from the genetic specificity within a species, the experimental environments, and the skillfulness of instillation
Summary
Idiopathic pulmonary fibrosis (IPF) is characterized by lung inflammation and abnormal tissue repair brought about by cytokines and interactions between several cell types, resulting in the expression of collagen gene and subsequent collagen deposition in the lungs (Piguet et a/., 1990; Gross and Hunninghake, 2001; GharaeeKermani and Phan, 2005). 1994a, b, 1996; Kuwano et a/., 2001; Gharaee-Ker-. Bleomycin (BLM) is a potent chemotherapeutic antitumor agent derived from Streptomyces verticil/us (Adamson, 1976; Umezawa, 1967); it is known to induce toxic side effects such as pulmonary fibrosis in humans as well as in experimental animals. The BLM-induced pulmonary fibrosis model is widely used for the study of the mechanism of the disease and M.-J. Its treatment (Jordana et a/., 1988; Sakanashi et a/., 1994; Gharaee-Kermani et a/., 2005; Moeller et a/., 2008). It is very important to determine the onset and severity of inflammation and fibrosis in studies of pathogenesis and therapy since the severity of induced disease using the same method and dose of BLM can be different from the genetic specificity within a species, the experimental environments, and the skillfulness of agent instillation. A noninvasive monitoring method is needed for the selection of proper animals with adequate severity of disease
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