Induction of p21^WAF/CIP1 during Hyperoxia

Abstract

p21WAF/CIP1 is an important regulator of cell cycle progression (1-4). When induced, p21WAF/CIP1 protein inhibits cell cycle progression at the G1/S interface, resulting in growth arrest of the cell. To determine if p21WAF/CIP1 is involved in growth arrest and lung injury during hyperoxia, several cell lines were exposed to high levels of hyperoxia. p21WAF/CIP1 was found to be induced by 72 h in all three cell lines. Next, using an in vivo model, p21WAF/CIP1 was found to be induced at both the mRNA and protein level in neonatal murine lung born and maintained in hyperoxia. Localization of p21WAF/CIP1 was found in the peripheral airway cells. Hyperoxia-induced p21WAF/CIP1 expression was then shown to be mediated through the p53 pathway, using adult p53 mutant mice. These studies demonstrated that p21WAF/CIP1 is induced both in cells grown in culture and in neonatal and adult lung exposed to high levels of hyperoxia. Localization of p21WAF/CIP1 expression to the peripheral airway cells suggests that p21WAF/CIP1 may act to inhibit growth of alveoli in neonatal lung and delay repopulation of alveolar cells during hyperoxic administration.

Differential Response of the Epithelium and Interstitium in Developing Human Fetal Lung Explants to Hyperoxia

“…Evidence from studies performed in vitro shows that cell growth and death are regulated by (de-)activation of oxygen-sensitive proteins and genes. These include some members of the cyclindependent kinase family of cell-cycle regulatory proteins (32) and hypoxia-inducible factor 1 (33). Additional factors such as heme oxygenase-1 (34) are known to regulate activation of signal transduction pathways linked with cell proliferation and cell cycle arrest.…”

Neonatal Hyperoxia Contributes Additively to Cigarette Smoke–Induced Chronic Obstructive Pulmonary Disease Changes in Adult Mice

“…Perinatal stresses, such as hyperoxia, have been shown to induce p53 and p21. These genes act as checkpoint regulators in the cell cycle and, when induced by stress, can lead to cell cycle growth arrest (3). Induction of these genes during a critical period of postnatal lung growth can cause alveolar growth inhibition, resulting in enlarged, simplified, and fewer alveoli in the mature lung.…”

“…Induction of these genes during a critical period of postnatal lung growth can cause alveolar growth inhibition, resulting in enlarged, simplified, and fewer alveoli in the mature lung. In contrast to the changes that occur in the lung with smoke-induced chronic obstructive lung disease (COPD), hyperoxia-induced alveolar growth inhibition has not been associated with significant matrix breakdown or cell death (3)(4)(5). Similar to the COPD lung, however, lung parenchymal changes due to early postnatal hyperoxia exposure have been shown to be associated with altered lung mechanics and decreased lung elastance in adult mice (6).…”

Increase in p21 expression independent of the p53 pathway in bleomycin-induced lung fibrosis

“…The p53 pathway was found to be involved upon exposure of lung epithelial cells to either hyperoxia (Barazzone et al, 1998;McGrath, 1998;O'Reilly et al, 1998) or to a number of DNA-damaging agents and carcinogens (Corroyer et al, 1996;Fujishita et al, 1995;Gadbois and Lehnert, 1997;Guinee et al, 1996). The expression of p16 (Sabourin et al, 1998), p21 (Guinee et al, 1996;McGrath, 1998), Rb (Fujishita et al, 1995;Sabourin et al, 1998), c-jun (Dolan et al, 1994;Haase et al, 1997), c-Fos (Haase et al, 1997), TNF-a (Lee and Rannels, 1998;Yao et al, 1998), TGFh (Lee and Rannels, 1998), BAX (Guinee et al, 1997), and Bcl-2 (Guinee et al, 1997) was reported to be influenced by a number of DNA-damaging agents and pollutants but the exact mechanism is still unclear.…”