Quantitative Proteomics Identifies Cannabinoid Receptor 2 as Candidate Marker of Idiopathic Pulmonary Fibrosis and Dysregulation of Endogenous Cannabinoids Pathway

Background: Idiopathic pulmonary fibrosis (IPF) a chronic, progressive, and lung fibrosis disease of unknown etiology with less effective treatment. It is important to discover new biomarker and therapeutic target for the diagnosis and cure of IPF. Method: Differential metabolic profiles may be useful for the diagnosis of IPF and provide additional insight into the molecular mechanisms underlying IPF. Plasma samples from IPF, COPD and normal controls were investigated using liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS) and these datasets were analyzed using multiple pattern performance methods. Multivariate statistical methods, pathway enrichment analysis and univariate receiver operating characteristic (ROC) curve analysis were performed. Results: OPLS-DA results showed that it exhibited significant separation between any two groups. ROC curve analyses revealed that 8 metabolites with high AUC above 0.7 between three groups in the plasma samples. Pathway analysis revealed that 3 metabolites are involved in endogenous cannabinoids/cannabinoid receptor 2 (CB2) signaling. Moreover, we found that the specific elevation of CB2 could be a signature of PF(Pulmonary Fibrosis) lung tissues in rat model. Conclusions: LC-MS-based plasma metabolomics provides a important tool to identify the potential biomarkers for IPF. Taken together, we performed quantitative chemoproteomic profiling and identified endogenous cannabinoids/CB2 as the key target of ICA in bleomycin-induced pulmonary fibrosis. Trial Registration: The study was approved by the the Ethics Committee of Huashan Hospital, Fudan University (KY2021-453)

Control of pain initiation by endogenous cannabinoids

The landmark paper discussed in this chapter, published by Calignano et al. in 1998, focuses on the control of pain initiation by endogenous cannabinoids. In the paper, analgesic lipid mediators are shown to be present in peripheral paw tissue where they control the ability of pain signals to ascend to the central nervous system (CNS). Anandamide acts through a peripheral mechanism to suppress inflammatory pain via cannabinoid type 1 receptors. Palmitoylethanolamine, subsequently identified as an endogenous ligand for peroxisome proliferator-activated receptor-α‎, produces peripheral antinociceptive effects via a mechanism similar to that for the cannabinoid type 2 receptor. These lipids do not serve redundant functions and, in combination, produce synergistic antinociceptive effects. These observations suggested that drug-development efforts targeting peripheral control of pain may elucidate improved pharmacotherapies that lack the unwanted CNS side effects of current treatments.