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A6232 - Epithelial LOX-1 Induction Modulates Acute Pulmonary Inflammation During Pneumonia
Author Block: E. Symer1, Y. Kim1, L. Washington1, M. R. Jones2, J. P. Mizgerd2, K. Traber3, L. J. Quinton4; 1Pulmonary Center, Boston University School of Medicine, Boston, MA, United States, 2Boston Univ School of Med, Boston, MA, United States, 3Boston Univ School of Med, Boston Med Ctr, Boston, MA, United States, 4Pulm Ctr, Boston Univ Sch of Med, Boston, MA, United States.
Rationale: Acute lower respiratory infections are a worldwide public health crisis. In the United States, pneumonia represents the leading infectious cause of death, and is the most common cause of childhood hospitalization, despite the use of antibiotics and vaccines targeting the common pathogens associated with lung infection. In order to develop new clinical interventions for patients with or at risk for pneumonia, a better understanding of the host pathways governing immune resistance and tissue resilience within the lung is greatly needed. Transcriptional profiling of mouse lung epithelium during pneumonia revealed induction of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a scavenger receptor largely known for its role in promoting vascular injury in the setting of atherosclerosis. The goal of this study was to evaluate the regulation and roles of pulmonary LOX-1 during pneumonia.
Methods / Results: Lung epithelial cells were FACS-purified from the lungs of pneumonic C57BL/6 mice 0 or 24h after intratracheal (i.t.) Escherichia coli, and LOX-1 mRNA induction was confirmed using qRT-PCR. LOX-1 gene expression was associated with markedly increased whole lung LOX-1 protein expression. In vitro, MLE12 cells, an alveolar epithelial cell line, exhibited significant upregulation of LOX-1 mRNA following stimulation with E. coli or pneumonic brochoalveolar lavage fluid (BALF) when compared to cells treated with media alone or control BALF (from uninfected mice), respectively. To determine the influence of LOX-1 on pneumonia outcome, mice received co-instillations of E. coli with neutralizing anti-LOX-1 IgG or control IgG. 24h after i.t. E. coli, LOX-1 blockade did not alter BALF cellularity or lung bacterial burdens. Interestingly, however, LOX-1 neutralization exacerbated alveolar edema, as evidenced by significant increases BALF total protein content, and worsened injury occurred concomitantly with elevated inflammatory cytokine concentrations.
Conclusions: Our data are the first to reveal LOX-1 induction in lung epithelium during pneumonia, where it may have a protective role against acute lung injury. This result was surprising given a wealth of evidence linking LOX-1 to inflammatory injury, albeit in different experimental and clinical settings. Future studies are required to better determine when, where and how LOX-1 regulation mediates acute pulmonary inflammation.