Abstract
The pathogenic mechanisms of acute lung injury due to direct and indirect pulmonary insults are incompletely understood. Using an unbiased, discovery and quantitative proteomic approach, we examined bronchoalveolar lavage fluid (BALF) proteome following lipopolysaccharide (LPS)-induced direct and indirect lung injury in mice. A total of 1017 proteins were both identified and quantitated in BALF from control, intratracheal (I.T., direct) and intraperitoneal (I.P., indirect) LPS-treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS; however, the magnitude of activation was much greater in the I.T. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation, and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. but suppressed by I.P. LPS. Cxcl15 (also known as lungkine) was also up-regulated by I.T. but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities, as well as significant differences in BALF protein expression profiles between LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury resulted in suppression of select components of lung innate immunity.
Highlights
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs that develops in response to direct or indirect insults to the alveolar–capillary membrane, resulting in increased permeability with subsequent interstitial/alveolar edema and diffuse alveolar damage [1]
Using isobaric tags for relative and absolute quantitation technology, Bhargava and colleagues characterized bronchioalveolar lavage fluid (BALF) protein expression profiles of ARDS survivors and non-survivors at different stages of disease progression and found that non-survivors manifested decreased expression of proteins related to coagulation, iron homeostasis and immune activation, but increased expression of proteins related to glycolysis, collagen metabolism and the actin cytoskeleton [11]
Schnapp et al identified a total of 870 proteins in BALF from three ARDS patients and further showed that insulin-like growth factor (IGF) and IGF binding protein-3 expression levels in BALF correlated with ARDS progression [12]
Summary
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs that develops in response to direct (pulmonary) or indirect (extra-pulmonary) insults to the alveolar–capillary membrane, resulting in increased permeability with subsequent interstitial/alveolar edema and diffuse alveolar damage [1]. Unbiased discovery and the quantitative proteomic approach is a powerful tool for identifying novel biomarkers and regulatory signaling networks in lung diseases including ARDS [8]. Using isobaric tags for relative and absolute quantitation technology, Bhargava and colleagues characterized BALF protein expression profiles of ARDS survivors and non-survivors at different stages of disease progression and found that non-survivors manifested decreased expression of proteins related to coagulation, iron homeostasis and immune activation, but increased expression of proteins related to glycolysis, collagen metabolism and the actin cytoskeleton [11]. The above BALF proteomic studies provided new insights into the pathogenesis of ARDS and identified novel therapeutic targets for ARDS treatment. These studies did not differentiate between pulmonary and extra-pulmonary ARDS, and the differences in BALF protein expression profiles between these two ARDS sub-groups are unknown
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