Sublethal Hyperoxia Impairs Pulmonary Innate Immunity

Abstract

Supplemental oxygen is often required in the treatment of critically ill patients. The impact of hyperoxia on pulmonary host defense is not well-established. We hypothesized that hyperoxia directly impairs pulmonary host defense, beyond effects on alveolar wall barrier function. C57BL/6 mice were kept in an atmosphere of >95% O2 for 4 days followed by return to room air. This exposure does not lead to mortality in mice subsequently returned to room air. Mice kept in room air served as controls. Mice were intratracheally inoculated with Klebsiella pneumoniae and followed for survival. Alveolar macrophages (AM) were harvested by bronchoalveolar lavage after 4 days of in vivo hyperoxia for ex vivo experiments. Mortality from pneumonia increased significantly in mice exposed to hyperoxia compared with infected mice in room air. Burden of organisms in the lung and dissemination of infection were increased in the hyperoxia group whereas accumulation of inflammatory cells in the lung was impaired. Hyperoxia alone had no impact on AM numbers, viability, or ability to phagocytize latex microbeads. However, following in vivo hyperoxia, AM phagocytosis and killing of Gram-negative bacteria and production of TNF-α and IL-6 in response to LPS were significantly reduced. AM surface expression of Toll-like receptor-4 was significantly decreased following in vivo hyperoxia. Thus sublethal hyperoxia increases Gram-negative bacterial pneumonia mortality and has a significant adverse effect on AM host defense function. Impaired AM function due to high concentrations of supplemental oxygen may contribute to the high rate of ventilator-associated pneumonia seen in critically ill patients.

Antioxidants improve antibacterial function in hyperoxia-exposed macrophages

“…Several studies have suggested that hyperoxia impairs pulmonary immunity and increases the risk of invasive pulmonary infection. Baleeiro and associates found that mice exposed to hyperoxia had increased mortality associated with gram-negative bacterial pneumonia compared to mice exposed to RA [4]. An increased bacterial burden and dissemination of the infection was also noted at the time of autopsy in the mice exposed to hyperoxia [4].…”

“…Bacterial adherence leading to colonization is the first step in the process of invasive pulmonary infection, with phagocytosis by alveolar macrophages critically important in preventing invasive pulmonary infection. Several studies have suggested that hyperoxia impairs pulmonary immunity and increases the risk of invasive pulmonary infection in newborn animal models and preterm infants (2)(3)(4)(5)(6). In fact, the STOP-ROP study suggested that preterm infants receiving higher inspired oxygen concentrations had an increased incidence of pneumonia and BPD, although the study was not designed to specifically examine this outcome [2].…”

Defective Phagocytosis and Clearance of Pseudomonas aeruginosa in the Lung Following Bone Marrow Transplantation

“…Rather, it may be that BMT AMs are defective due to the persistent lack of supportive factors from structural/resident cells within the BMT lung. It is possible that the conditioning regimen (irradiation) alters the ability of the pulmonary parenchymal cells, especially alveolar epithelial cells, to support AM differentiation in the lung (36).…”

Lysophosphatidic acid generation by pulmonary NKT cell ENPP-2/autotaxin exacerbates hyperoxic lung injury

“…Different lung disease models such as asthma and more recently hyperoxia-induced lung injury could be linked to NKT cell-induced immune responses [1,[3][4][5][6][7]. Hyperoxia remains a mainstay in clinical patient care in order to improve oxygen delivery to crucial organs in critically ill patients suffering from acute lung injury or during cardiac surgery to name a few [3].…”

“…Hyperoxic lung injury is typically characterized by alveolar epithelial as well as endothelial damage. These effects result in a capillary leak syndrome followed by inflammatory cell recruitment [4][5][6].…”