3-nitrotyrosine and Syndrome

Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Bronchiolitis obliterans syndrome (BOS), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. We investigated, using transgenic mice, the mechanisms through which the deficiency of IL-1β/IL-18, Casp-1, or Fpr-1 genes could be protective in an experimental model of BOS, induced in mice by allogeneic heterotopic tracheal transplantation. Fpr-1 KO mice showed a marked reduction in histological markers of BOS and of mast cell numbers compared to other groups. Molecular analyses indicated that the absence of the Fpr-1 gene was able to decrease NF-κB nuclear translocation and modulate NLRP3 inflammasome signaling and the mitogen-activated protein kinase (MAPK) pathway in a more significant way compared to other groups. Additionally, Fpr-1 gene deletion caused a reduction in resistance to the apoptosis, assessed by the TUNEL assay. Immunohistochemical analyses indicated changes in nitrotyrosine, PARP, VEGF, and TGF-β expression associated with the pathology, which were reduced in the absence of the Fpr1 gene more so than by the deletion of IL-1β/IL-18 and Casp-1. We underline the importance of the NLRP3 inflammasome and the pathogenic role of Fpr-1 in experimental models of BOS, which is the result of the modulation of immune cell recruitment together with the modulation of local cellular activation, suggesting this gene as a new target in the control of the pathologic features of BOS.

Topics: Animals; Apoptosis; Bronchiolitis Obliterans; Caspase 1; Cell Count; Enzyme Activation; Inflammasomes; Intercellular Signaling Peptides and Proteins; Interleukin-18; Interleukin-1beta; Male; Mast Cells; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Nitric Oxide Synthase Type II; NLR Family, Pyrin Domain-Containing 3 Protein; Poly(ADP-ribose) Polymerases; Receptors, Formyl Peptide; Signal Transduction; Syndrome; Tyrosine

Bladder pain syndrome/interstitial cystitis (BPS/IC) includes a heterogeneous collection of underlying pathological conditions. Compared to the classic IC with a Hunner lesion, now denominated ESSIC type 3C, the non-Hunner type of BPS/IC appears different in a number of respects. In a previous study, measuring luminal nitric oxide (NO) in the bladder of patients with BPS/IC, it was reported that all patients with ESSIC type 3C had high levels of NO. The aim of the present study was to investigate the source of inducible nitric oxide synthase (iNOS) and thereby the cellular origin of NO production via iNOS.. Immunohistochemistry, with two different anti-iNOS antibodies, was used to study 10 patients with BPS/IC ESSIC type 3C who expressed high levels of intraluminal NO. These results were compared with four patients with non-Hunner BPS/IC. To substantiate further the involvement of iNOS in this condition, the protein expression of nitrotyrosine, a marker for iNOS activation, was also assessed.. On routine histopathology, the tissues of type 3C patients exhibited inflammatory infiltrates of varying intensity. Strong immunoreactivity for both iNOS and nitrotyrosine was noted within the urothelium but also within the inflammatory infiltrates in the lamina propria of these subjects.. The findings of a clearly detectable protein expression of iNOS in both the urothelium and the inflammatory infiltrates in bladder biopsies from patients with BPS/IC ESSIC type 3C suggest that the production of NO, in this entity, may occur in different tissue compartments.

Topics: Biomarkers; Biopsy; Cystitis, Interstitial; Humans; Inflammation; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type II; Retrospective Studies; Syndrome; Tyrosine; Urinary Bladder; Urinary Bladder Diseases; Urothelium