Novel protein pathways in development and progression of pulmonary sarcoidosis

Abstract

Pulmonary involvement occurs in up to 95% of sarcoidosis cases. In this pilot study, we examine lung compartment-specific protein expression to identify pathways linked to development and progression of pulmonary sarcoidosis. We characterized bronchoalveolar lavage (BAL) cells and fluid (BALF) proteins in recently diagnosed sarcoidosis cases. We identified 4,306 proteins in BAL cells, of which 272 proteins were differentially expressed in sarcoidosis compared to controls. These proteins map to novel pathways such as integrin-linked kinase and IL-8 signaling and previously implicated pathways in sarcoidosis, including phagosome maturation, clathrin-mediated endocytic signaling and redox balance. In the BALF, the differentially expressed proteins map to several pathways identified in the BAL cells. The differentially expressed BALF proteins also map to aryl hydrocarbon signaling, communication between innate and adaptive immune response, integrin, PTEN and phospholipase C signaling, serotonin and tryptophan metabolism, autophagy, and B cell receptor signaling. Additional pathways that were different between progressive and non-progressive sarcoidosis in the BALF included CD28 signaling and PFKFB4 signaling. Our studies demonstrate the power of contemporary proteomics to reveal novel mechanisms operational in sarcoidosis. Application of our workflows in well-phenotyped large cohorts maybe beneficial to identify biomarkers for diagnosis and prognosis and therapeutically tenable molecular mechanisms.

Identification of Dysregulated Mechanisms and Candidate Gene Markers in Chronic Obstructive Pulmonary Disease

“… 46 , 47 PGM1 has been linked to lung disease through multiple metabolic pathways. 48 , 49 PRRG4 has been shown to be differentially expressed in COPD patients, 50 and the present study not only confirms that finding but extends it by showing aberrant methylation of the gene. Therefore, the altered expression of PRRG4 in COPD may reflect altered gene methylation.…”

Plasmolipin and Its Role in Cell Processes

“…A lower PLLP content in bronchoalveolar lavage fluid was observed in sarcoidosis patients by a proteome analysis. In addition, substantial proteome changes were observed to implicate various cytokines in sarcoidosis [ 96 ]. It should be noted that there is an inverse correlation between PLLP expression and expression of the genes for certain cytokines and growth factors (IL-1, IL-6, IL-8, and VEGFA), indicating indirectly that PLLP may be involved in regulating expression of these genes [ 83 , 84 , 97 – 101 ].…”

The Role of Oxidative Stress in Sarcoidosis

“…However, the finding that novel mutation combinations were solely expressed in disease indicates that a mitochondrial-mediated pathogenic pathway may underlie both IPF and sarcoidosis [ 65 ]. Further proof that dysmetabolism in the mitochondria is responsible for the altered redox balance in sarcoidosis come from an elegant proteomic study conducted on BALF [ 66 ]. In this pilot study, Bhargava et al characterized the proteins in BAL cells from 4 controls and 4 sarcoidosis cases matched for age, sex, race, and smoking status.…”