Bronchopulmonary dysplasia (BPD) commonly develops in premature infants. An improved understanding of the pathophysiology of BPD requires better models. In this study, neonatal FVB/N mice were exposed to room air or 85% oxygen for 28 days. Neonatal hyperoxia resulted in decreased alveolar septation, increased terminal air space size, and increased lung fibrosis. These changes were evident after 7 days and more pronounced by 28 days. Decreased alveolarization was preceded by decreased proliferation of lung cells. After 3 days of hyperoxia, cell proliferation was decreased compared with room air littermates. Cell proliferation continued to be decreased in the first 2 wk but normalized by 4 wk. Hyperoxia caused an increased number of inflammatory cells in lung tissue and in lung lavage fluid. Analysis of lung tissue RNA by RT-PCR showed that hyperoxia increased expression of the proinflammatory cytokines interleukin-1α and macrophage inflammatory protein-1α. Prolonged neonatal hyperoxia caused functional changes, decreasing lung volume and pulmonary compliance. We conclude that prolonged exposure of neonatal mice to hyperoxia creates a lesion that is very similar to human BPD and suggests that altered cell proliferation may be important in the pathogenesis of chronic neonatal lung disease.

The stress response and stress proteins confer protection against diverse forms of cellular and tissue injury, including acute lung injury. The stress response can inhibit nonstress protein gene expression, therefore transcriptional inhibition of proinflammatory responses could be a mechanism of protection against acute lung injury. To explore this possibility, we determined the effects of the stress response on nuclear translocation of the transcription factor NF-B, an important regulator of proinflammatory gene expression. In

The importance of reactive oxygen species (ROS) or changes in cellular redox state in signal transduction and gene regulation is becoming increasingly evident. In this study, we tested the hypothesis that ROS are directly involved in the induction of the mitochondrial antioxidant manganese superoxide dismutase (MnSOD) and mediate the induction of MnSOD by tumor necrosis factor-alpha (TNF-alpha). Pretreatment of human pulmonary adenocarcinoma cells H441 with the antioxidants N-acetyl-L-cysteine (NAC) and nordihydroguaiaretic acid (NDGA) blocked MnSOD induction by TNF-alpha, implicating ROS as a signaling agent in this pathway. Treatment of H441 cells with the exogenous oxidants hydrogen peroxide (H2O2) and diamide increased MnSOD mRNA, supporting the hypothesis that ROS directly affect expression of MnSOD. The temporal pattern of MnSOD induction differed for TNF-alpha and H2O2, suggesting distinct signaling pathways. DNA binding of two redox-sensitive transcription factors, NF-kappa B and activator protein (AP)-1, was evaluated. TNF-alpha increased nuclear factor (NF)-kappa B-DNA binding, an effect blocked by pretreatment with NAC. H2O2 did not alter NF-kappa B-DNA binding. There was no evidence of AP-1 binding in cells treated with either TNF-alpha or H2O2. We conclude that ROS directly alter MnSOD expression and are involved in the induction of MnSOD by TNF-alpha.

No abstract

The stress response is a highly conserved cellular defense mechanism defined by the rapid and specific expression of stress proteins, with concomitant transient inhibition of nonstress protein gene expression. The stress proteins mediate cellular and tissue protection against diverse cytotoxic stimuli. Among the many classes of stress proteins, heat shock protein 70 and heme oxygenase-1 are the best characterized with respect to lung biology. A potential role for stress proteins in human lung disease is inferred from studies demonstrating stress protein expression in the lungs of patients with cancer, asthma, and acute lung injury. Several examples of stress protein-mediated cytoprotection exist in cell and animal models of acute lung injury. Stress protein induction protects rats against acute lung injury caused by either systemic administration of endotoxin or intratracheal administration of phospholipase A1. In vitro, increased expression of stress proteins protects lung cells against endotoxin-mediated apoptosis and oxidant injury. The mechanisms of stress response-mediated cytoprotection may involve the enzymatic and molecular chaperone properties of stress proteins. Alternatively, the stress response may protect by modulating lung proinflammatory responses. Data from extrapulmonary systems suggest that stress response-associated factors (heat shock protein 70 and heat shock factor) are directly involved in modulation of proinflammatory gene expression. Recent evidence also demonstrates interactions between the stress response and the I-kappa B/nuclear factor-kappa B pathway in cultured lung cells. Increased understanding about the role of stress proteins in lung biology may support efforts to selectively increase expression of one or more stress proteins to provide protection against human acute lung injury.