PURPOSE: Oxidant/antioxidant imbalance has been suggested to play an important role in the pathogenesis of secondary pulmonary hypertension in bleomycin-induced lung fibrosis. N-acetyl-L-cysteine(NAC) is being used, in addition to prednisone, and/or azathioprine in treatment of lung fibrosis. The side effects of NAC in IPF may be dosage dependent and need to be further explored.
METHODS: Male Wistar rats (n=20) were studied. (Group I, BLM Group) received intratracheal bleomycin (7 units/kg). Group II (NAC+BLM group), first received oral NAC daily for 7 days and intratracheal bleomycin was administered on the 8th day. NAC was then daily administered till the animals were sacrificed on Day 28. The lung histopathology was examined and compared to control (Group III). Morphometric evaluation of the bronchioles (50 to 200 μm diameter) was done using Nikon 90i fully motorized trinocular microscope and image analyzer. The accompanying pulmonary arterioles were assessed and their tunica media were measured.
RESULTS: High dose NAC (3 mmol/kg) administration in Group II was associated with a significant increase in arteriolar muscularisation on Day 28 (26.16 µm, P=0.004), on comparison with BLM group(19.80 µm). At low dose NAC (0.3 mmol/kg) in Group II, on day 28, there was no difference in muscularisation (18.83µm) on comparison with BLM group(19.80 µm). On comparing with control (12.64 µm) a significant increase in muscularisation of the arterioles was seen on BLM administration on day 28 (19.80 µm. P<0.0001).
CONCLUSIONS: A significant difference of pulmonary arteriolar muscularisation on Day 28, between the two doses of NAC (p=0.025) was observed in BLM model.
CLINICAL IMPLICATIONS: The antioxidant NAC is used in the treatment of pulmonary fibrosis. The vascular effects of NAC are dose dependent and manifest as muscularisation of pulmonary arterioles on Day 28. NAC may lead to the development of PAH on long term use in pulmonary fibrosis patients and needs to be monitored in all cases.
DISCLOSURE: The following authors have nothing to disclose: Ritu Kulshrestha, D. Soundarya, A. Dinda, Krishnan Ravi
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