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  • In this study it was demonstrated that also in mice

    2022-01-13

    In this study it was demonstrated that also in mice chronically exposed to CS, lung inflammation persists after SC and is associated with a progressive alveolar loss and remodeling of respiratory tract, characterized by the onset of bronchial and bronchiolar GCM and peribronchiolar fibrosis. Persistent inflammation is characterized in these mice by an increased cellularity with a significant increase of neutrophils and macrophages in the peripheral structure of the lung and a persistent activation of NF-κB associated with a nuclear localization of the p65 (RelA) component of the complex that modulates transcription of target genes. In particular, RelA can enhance the transcription of a series of downstream target genes such as proinflammatory or anti-inflammatory cytokines and chemokines (ie, KC, MIP-1β, IL-6, and IL-10) or Rifapentine (such as macrophage metalloprotease-12, arginase 1) and factors (ie, FGF-1, PAR-1, and IL-13), which have been implicated in alveolar destruction or in peribronchiolar and bronchial remodeling. In particular, up-regulation of genes encoding the attractants CXCL1/KC (the murine IL-8 homolog) and chemokine (C-C motif) ligand 4/MIP-1β would explain the prolonged presence of polymorphonuclear leukocytes and macrophages in peripheral lung structures of mice after SC, whereas the increased expression of arginase 1 and FGF-138, 39 could explain the consistent collagen deposition in peribronchiolar areas. In addition, the strong macrophage metalloprotease-12 expression coincided with the progression phase of the disease probably for enzyme destruction of alveolar structures by macrophages. A link between PAR-1 and IL-13 overexpression and development of GCM may be postulated on the basis of our recent work and other ones published on this matter.32, 41 FPRs belong to the family of pattern recognition receptors, G-protein–coupled receptor family that regulate innate immune responses. Three FPRs have been identified in humans: FPR-1, FPR-2, and FPR-3, which have been described across several species, including mouse. Distinct to the other member of the FPR family, the function of FPR-3 remains relatively poorly understood. FPR-1 and FPR-2 have diverse roles in the initiation, propagation, and resolution of inflammation. Murine orthologs of human FPR-1 and FPR-2 share a relative high sequence homology, are expressed on similar cell types (neutrophils, macrophages, monocytes, fibroblasts, epithelial, and endothelial cells), and induce the same effects of neutrophil chemotaxis, degranulation, reactive oxygen species production, and phagocytosis. FPR-1 was originally identified in phagocytic leukocytes and mediates cell chemotaxis and activation in response to the bacterial formylated chemotactic peptides (eg, formyl-methionyl-leucyl phenylalanine). Agonist binding to FPR-1 elicits a signal transduction cascade involving phosphatidylinositol 3-kinase, protein kinase C, mitogen-activated protein kinases, and the transcription factor NF-κB. Unlike FPR-1 that is expressed at high levels in both peripheral blood monocytes and neutrophils, FPR-2 is prevalently expressed in monocytes. Signals on both receptors can induce neutrophil recruitment to sites of inflammation, reactive oxygen species production, degranulation, and cytokine release as well as FPR signaling can induce an alternatively activated phenotype in macrophages that express IL-13, IL-4, and arginase that uses arginine to produce proline, an essential amino acid for collagen synthesis. Although FPRs were initially thought to bind only N-formylated peptides of bacterial origin (which are recognized as potent pathogen-associated molecular patterns), FPRs also bind mitochondrial formylated peptides (damage-associated molecular patters) released from the cell after necrotic cell death, and other inflammatory nonformylated ligands that include cathepsin G, serum amyloid A, and β amyloid or anti-inflammatory agonist such as annexin A1 and lipoxin A4.