Abstract
Acute lung injury (ALI) is characterized by pulmonary edema and acute inflammation leading to pulmonary dysfunction and potentially death. Early medical intervention may ameliorate the severity of ALI, but unfortunately, there are no reliable biomarkers for early diagnosis. We screened for biomarkers in a mouse model of ALI. In this model, inhalation of S. aureus enterotoxin A causes increased capillary permeability, cell damage, and increase protein and cytokine concentration in the lungs. We set out to find predictive biomarkers of ALI in bronchoalveolar lavage (BAL) fluid before the onset of clinical manifestations. A cutting edge proteomic approach was used to compare BAL fluid harvested 16 h post S. aureus enterotoxin A inhalation versus BAL fluid from vehicle alone treated mice. The proteomic PF 2D platform permitted comparative analysis of proteomic maps and mass spectrometry identified cytochrome b5 and cytokeratin 17 in BAL fluid of mice challenged with S. aureus enterotoxin A. Validation of cytochrome b5 showed tropic expression in epithelial cells of the bronchioles. Importantly, S. aureus enterotoxin A inhalation significantly decreased cytochrome b5 during the onset of lung injury. Validation of cytokeratin 17 showed ubiquitous expression in lung tissue and increased presence in BAL fluid after S. aureus enterotoxin A inhalation. Therefore, these new biomarkers may be predictive of ALI onset in patients and could provide insight regarding the basis of lung injury and inflammation.
Highlights
Pulmonary biomarkers are needed to predict the clinical course of lung disease, status, progression, and response to treatment [1,2]
Lung sections stained by hematoxylin and eosin (H&E) showed leakage of red blood cells from blood vessels into the alveoli (Fig. 1A, black arrows in upper right panel), abundant leukocyte infiltration in the peri-vascular tissue, and increased cellularity in the interstitium and alveolar space as we observed previously [11]
Cytochrome b5 expression was restricted to epithelial cells of the bronchioles and S. aureus enterotoxin A (SEA) inhalation decreased the intensity of its signal
Summary
Pulmonary biomarkers are needed to predict the clinical course of lung disease, status, progression, and response to treatment [1,2]. During acute lung injury (ALI), several factors correlate with tissue damage such as recruitment of neutrophils and macrophages, and increases in IFNc in BAL fluid [3]. These events occur late in the disease process, once ALI is fully initiated. There are other causes such as exposure to aerosolized toxic chemicals, aspiration, and multiple trauma. Even in these cases, a secondary infection may trigger the inflammatory response that leads to ALI [6]. Unlike infection with whole organisms, LPS does not stimulate T cells, which likely make a substantial contribution to disease in humans
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