Pregnancy Zone Protein Is Associated with Airway Infection, Neutrophil Extracellular Trap Formation, and Disease Severity in Bronchiectasis

Abstract

Rationale: PZP (pregnancy zone protein) is a broad-spectrum immunosuppressive protein believed to suppress T-cell function during pregnancy to prevent fetal rejection. It has not previously been reported in the airway.Objectives: To characterize PZP in the bronchiectasis airway, including its relationship with disease severity.Methods: Label-free liquid chromatography/mass spectrometry was performed for sputum protein profiling of patients with bronchiectasis confirmed by high-resolution computed tomography. Results for patients with and without Pseudomonas aeruginosa infection were compared. Sputum and serum PZP was measured by validated ELISA. Airway infection status was established by culture and 16S ribosomal RNA sequencing. Immunofluorescence, ELISA, and electron microscopy were used to identify the cellular source of PZP in neutrophils treated with multiple stimuli.Measurements and Main Results: Elevated PZP was identified by label-free liquid chromatography/mass spectrometry as being associated with P. aeruginosa infection. In a validation study of 124 patients, sputum but not serum concentrations of PZP were significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations, and symptoms. Airway infection with Proteobacteria such as P. aeruginosa was associated with higher concentrations of PZP. PZP in sputum was directly related to airway bacterial load. Neutrophils induced to form neutrophil extracellular traps (NETs) with phorbol myristate acetate released high concentrations of PZP in vitro, and fluorescence microscopy confirmed the presence of PZP in NETs, whereas fluorescence and electron microscopy localized PZP to the cytoplasm and nuclei of neutrophils. Effective antibiotic therapy reduced sputum PZP.Conclusions: PZP is released into NETs. We report a novel link between airway infection, NET formation, and disease severity in bronchiectasis during chronic airway inflammation.

Discovery and validation of PZP as a novel serum biomarker for screening lung adenocarcinoma in type 2 diabetes mellitus patients

“…Moreover, elevated PZP has been identified as an indicator associated with P. aeruginosa infection. Sputum but not serum concentrations of PZP have been significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations and symptoms [ 34 ]. Previous research has also uncovered the role of PZP in cancers.…”

“…According to the HPA database, PZP is highly expressed in immune cells, including T cells and macrophages. In previous research, P. aeruginosa infection-induced PZP elevation was derived from neutrophils [ 34 ]. Therefore, serum PZP may be derived from tumor-related immune cells, but further studies still need to confirm the source of PZP and its diagnostic value by large-scale analysis.…”

<p>Prognostic Significance of Pregnancy Zone Protein and Its Correlation with Immune Infiltrates in Hepatocellular Carcinoma</p>

“…4 Furthermore, as a powerful T cell immunosuppressant for preventing rejection of the fetal allograft during pregnancy, PZP was associated with airway infection, disease severity in bronchiectasis during chronic airway inflammation. 15 However, in the previous studies, the relationship between PZP expression and tumor, especially HCC was not reported.…”

Serum exosomal pregnancy zone protein as a promising biomarker in inflammatory bowel disease

“…PZP is a broad-spectrum immunosuppressant with anti-protease activity. It was thought to have a role in pregnancy by inhibiting the cell-mediated immune response to prevent fetal rejection [ 23 ]. In addition, PZP has been shown to inhibit the immune reactivity of T lymphocytes, recruitment, migration, proliferation of T cells, and IL-2 production [ 24 , 25 ].…”