Evaluating the NET influence of inflammation on pneumonia biology.
Evaluating the NET influence of inflammation on pneumonia biology.
复制标题
评估炎症对肺炎生物学的 NET 影响。
DOI：
10.1164/rccm.201209-1702ed
复制
发表时间：
2012
影响因子：
24.7
通讯作者：
Quinton,LeeJ
中科院分区：
文献类型：
--
作者：
Quinton,LeeJ
Respiratory infections represent the greatest burden of disease worldwide, with a mortality rate that is virtually unchanged since the dawn of the antibiotic era (1). Although acute pulmonary inflammation is required for defense against invading microbes, it often comes at the expense of disrupted tissue homeostasis. Consequently, pneumonia is the leading cause of acute lung injury (2). At the forefront of this important but dangerous pulmonary immune response are neutrophils, which bear an armament of robust antimicrobial machinery, but can directly exacerbate inflammatory injury (3). In the context of infection, our community has long struggled to understand whether and how this delicate balance can be controlled.In this issue of the Journal, Barletta and colleagues (pp. 1044–1050) aim to determine the influence of adenosine A2B receptor signaling on pneumonia induced by Klebsiella pneumoniae (4). Previous reports have almost uniformly supported a tissueprotective role for signaling downstream of the A2B receptor in settings of lung injury, including that elicited by lipopolysaccharide (5, 6), mechanical ventilation (7), bleomycin (8), and hypoxia (9). Moreover, antiinflammatory phenotypes have coincided with evidence that adenosine (via A2B receptor) limits fundamental neutrophil functions such as migration (5, 6), oxidative burst (5), and phagocytosis (10). Based on the reciprocal relationship observed between A2B receptor signaling and neutrophilic inflammation, Barletta and coworkers hypothesized that deletion of this receptor would improve antibacterial host defense during pneumonia, a condition during which the role of A2B receptor signaling has never been explored. After all, it seems only natural that enhanced inflammation would generate a less favorable environment for bacteria. As anticipated, mice devoid of A2B receptor exhibited significantly less mortality in association with decreased bacterial burdens in the lungs and blood. Perhaps the most compelling finding of this study, however, is not what was different, but rather, what was not. By all accounts (airspace leukocytosis, cytokine expression, plasma extravasation, etc.), typical indices of innate immunity were unaffected by A2B receptor deficiency in pneumonic mice. At first glance, this contradicts the aforementioned reports of exaggerated pulmonary inflammation and worsened outcomes in A2B receptor–deficient mice (5–9). However, the pathology in those studies was solely driven by sterile inflammation, as opposed to here where the pathological response to live infection was subject to the complex dynamics of bacterial viability. In this particular instance wherein bacterial burdens were reduced, one may predict fewer neutrophils as a consequence of fewer inflammatory signals. As this is not the case, the results are in fact consistent with the antiinflammatory roles previously ascribed to this receptor. Interestingly, the authors provide several pieces of evidence that unequivocally implicate neutrophils in A2B receptor–dependent outcomes, despite equivalent neutrophil numbers. First, A2B receptor expression was far greater for lung neutrophils compared with other lung cells and even resting bone marrow neutrophils. Second, improved host defense was reproducible in chimeric mice lacking A2B receptor in hematopoietic cells alone. Last, neutrophil depletion significantly reduced the benefit of A2B receptor deficiency on antimicrobial defense. So although the quantitative aspects of neutrophilic alveolitis were insufficient to explain the protection afforded by A2B receptor deficiency, this cell type was nonetheless at the heart of the phenotype.
