Interstitial lung disease is thought to result from progression of an initial lung injury and alveolitis into a chronic inflammatory process that produces fibrosis. However, the relationship between the severity of the initial phase of acute injury and alveolitis and the amount of subsequent chronic inflammation and fibrosis remains unclear. We induced a wide spectrum of acute lung injury in rabbits by using various amounts of intratracheal bleomycin (5 or 10 U/kg) with and without oxygen supplementation (100% O2 for 2 min). The arterial oxygen tension on Day 12 after the bleomycin correlated with the extent of acute lung injury, as well as with the amount of chronic inflammation and fibrosis present on Day 56, as determined by physiologic parameters (lung volume, DlCO/Va, and PO2), and morphometry (volume proportions abnormal parenchyma made up of intra-alveolar macrophages, intra-alveolar granulocytes, abnormal alveoli, abnormal airways, fibrosis, consolidation, and honeycombing). We conclude that in bleomycin-induced interstitial lung disease in the rabbit, there is a direct relationship between the severity of acute lung injury after intratracheal bleomycin and the amount of subsequent chronic inflammation and fibrosis. This suggests that the mechanisms regulating the development of fibrosis are directly influenced by the extent of initial injury.