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CD40-CD40 ligand disruption does not prevent hyperoxia-induced injury.

ABSTRACT: Recent studies suggest that apoptosis plays a role in oxygen-induced injury, although the activation pathways and the executioner proteases that lead to cleavage of lung cell proteins and DNA, are not yet identified. We explored previously the tumor necrosis factor/tumor necrosis factor receptor and the Fas/FasL, belonging to the intrinsic pathway, and could not demonstrate any protective effect by interfering with these cell receptors. Lately, it has been shown that interacting with the CD40 system, also known to promote cell death, by administering anti-CD40 ligand (L) antibody was beneficial in several diseases and, in particular, in hyperoxia-induced injury. Using CD40- and CD40L-deficient mice (-/-) as well as administering anti-CD40L antibody, we examined the extent of lung injury in oxygen-breathing mice by several ways (lung weight, histology, inflammatory mediators, and DNA ladder) as well as the mortality. The development of lung injury was similar in wild-type, CD40-/-, CD40L-/-, or in wild-type mice treated with anti-CD40L antibody. Apoptosis was present in all conditions at 72 hours of oxygen exposure. These results show that oxygen-induced injury does not require CD40-CD40L interaction and that apoptosis of lung cells does not involve this pathway.

SUBMITTER: Barazzone Argiroffo C

PROVIDER: S-EPMC1867140 | biostudies-literature | 2002 Jan

REPOSITORIES: biostudies-literature

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CD40-CD40 ligand disruption does not prevent hyperoxia-induced injury.

Barazzone Argiroffo Constance C Donati Yves R YR Boccard Julien J Rochat Anne F AF Vesin Christian C Kan Chen-Da CD Piguet Pierre-François PF

The American journal of pathology 20020101 1

Recent studies suggest that apoptosis plays a role in oxygen-induced injury, although the activation pathways and the executioner proteases that lead to cleavage of lung cell proteins and DNA, are not yet identified. We explored previously the tumor necrosis factor/tumor necrosis factor receptor and the Fas/FasL, belonging to the intrinsic pathway, and could not demonstrate any protective effect by interfering with these cell receptors. Lately, it has been shown that interacting with the CD40 sy ...[more]

PMID: 11786400

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Project description:An important issue in critical care medicine is the identification of ways to protect the lungs from oxygen toxicity and reduce systemic oxidative stress in conditions requiring mechanical ventilation and high levels of oxygen. One way to prevent oxygen toxicity is to augment antioxidant enzyme activity in the respiratory system. The current study investigated the ability of aerosolized extracellular superoxide dismutase (EC-SOD) to protect the lungs from hyperoxic injury. Recombinant human EC-SOD (rhEC-SOD) was produced from a synthetic cassette constructed in the methylotrophic yeast Pichia pastoris. Female CD-1 mice were exposed in hyperoxia (FiO2>95%) to induce lung injury. The therapeutic effects of EC-SOD and copper-zinc SOD (CuZn-SOD) via an aerosol delivery system for lung injury and systemic oxidative stress at 24, 48, 72 and 96 h of hyperoxia were measured by bronchoalveolar lavage, wet/dry ratio, lung histology, and 8-oxo-2'-deoxyguanosine (8-oxo-dG) in lung and liver tissues. After exposure to hyperoxia, the wet/dry weight ratio remained stable before day 2 but increased significantly after day 3. The levels of oxidative biomarker 8-oxo-dG in the lung and liver were significantly decreased on day 2 (P<0.01) but the marker in the liver increased abruptly after day 3 of hyperoxia when the mortality increased. Treatment with aerosolized rhEC-SOD increased the survival rate at day 3 under hyperoxia to 95.8%, which was significantly higher than that of the control group (57.1%), albumin treated group (33.3%), and CuZn-SOD treated group (75%). The protective effects of EC-SOD against hyperoxia were further confirmed by reduced lung edema and systemic oxidative stress. Aerosolized EC-SOD protected mice against oxygen toxicity and reduced mortality in a hyperoxic model. The results encourage the use of an aerosol therapy with EC-SOD in intensive care units to reduce oxidative injury in patients with severe hypoxemic respiratory failure, including acute respiratory distress syndrome (ARDS).

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CD40-CD40 ligand disruption does not prevent hyperoxia-induced injury.

Publications

CD40-CD40 ligand disruption does not prevent hyperoxia-induced injury.

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