Hyperoxia Mediates Acute Lung Injury and Increased Lethality in MurineLegionellaPneumonia: The Role of Apoptosis

Abstract

Legionella pneumophila is a major cause of life-threatening pneumonia, which is characterized by a high incidence of acute lung injury and resultant severe hypoxemia. Mechanical ventilation using high oxygen concentrations is often required in the treatment of patients with L. pneumophila pneumonia. Unfortunately, oxygen itself may propagate various forms of tissue damage, including acute lung injury. The effect of hyperoxia as a cofactor in the course of L. pneumophila pneumonia is poorly understood. In this study, we show that exposure to hyperoxic conditions during the evolution of pneumonia results in a marked increase in lethality in mice with Legionella pneumonia. The enhanced lethality was associated with an increase in lung permeability, but not changes in either lung bacterial burden or leukocyte accumulation. Interestingly, accelerated apoptosis as evidenced by assessment of histone-DNA fragments and caspase-3 activity were noted in the infected lungs of mice exposed to hyperoxia. TUNEL staining of infected lung sections demonstrated increased apoptosis in hyperoxic mice, predominantly in macrophages and alveolar epithelial cells. In vitro exposure of primary murine alveolar epithelial cells to Legionella in conjunction with hyperoxia accelerated apoptosis and loss of barrier function. Fas-deficient mice demonstrated partial resistance to the lethal effects of Legionella infection induced by hyperoxia, which was associated with attenuated apoptosis in the lung. These results demonstrate that hyperoxia serves as an important cofactor for the development of acute lung injury and lethality in L. pneumophila pneumonia. Exaggerated apoptosis, in part through Fas-mediated signaling, may accelerate hyperoxia-induced acute lung injury in Legionella pneumonia.

Altered Inflammatory Responses in TLR5-Deficient Mice Infected with Legionella pneumophila

“…These in vitro phenotypes were found to be Myd88 (and likely also TLR5)-independent. Although Naip5 regulates intracellular multiplication of Legionella within macrophages in vitro, its effect on in vivo replication is considerably less dramatic, varying from negligible to ϳ10-fold differences in lung CFUs (7,9,40,41). In addition to NAIP5, IPAF has also been found to mediate recognition of Lp flagellin with TLR5-independent activation of caspase-1 and restriction of Lp replication (9,10).…”

The Chitinase-like Proteins Breast Regression Protein-39 and YKL-40 Regulate Hyperoxia-induced Acute Lung Injury

“…If they are confirmed in subsequent, larger studies, they also raise the possibility that the elevated levels of YKL-40 are causally related to the milder disease in these individuals. Oxidant injury also plays a major role in the pathogenesis of interstitial lung diseases, asthma, and chronic obstructive pulmonary disease and can worsen the effects of pulmonary infections (63)(64)(65)(66)(67). When viewed in combination, these observations allow for the speculation that BRP-39/YKL-40 may be able to be manipulated to control oxidant-induced pulmonary responses, and that the levels of circulating and or organ YKL-40 might be useful biomarkers that can predict the severity and or course of these disorders.…”

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

“…These studies reveal that apoptosis of epithelial cells occurs in hyperoxic lungs. The presence of apoptosis of hyperoxic epithelium was evaluated by the presence of oligonucleosomal DNA fragments as assessed by terminal dUTP nick end labeling (TUNEL) analysis, and specific internucleosomal DNA laddering, immunohistochemical and biochemical assays for apoptotic gene expression and activities [12,25,26,[35][36][37][38][39]. In addition, increased caspase activities have also been observed in hyperoxic lungs by several investigators [12,38,40].…”