Biomarkers of Fibroproliferative Healing in Fibrosing Idiopathic Interstitial Pneumonias

Abstract

Aims:The main feature of fibrosing idiopathic interstitial pneumonias (fIIPs) is the fibroproliferative potential of underlying pathogenetic process. We hypothesize that the concentration of potential markers of fibroproliferative healing, PAR-2, TGF-β1, TNF-α and IL-4Rα in bronchoalveolar lavage fluid (BALF) differ in patients with fIIPs compared to controls (C).Patients and Methods:10 patients with fIIPs and 9 controls (C) were included to the study.Concentrations of CD124 (IL4Rα), PAR-2, TGF-β1 and TNF-α in BALF were determined using the ELISA method.Results:We observed higher concentrations of IL4Rα (fIIPS 1499.4 pg/ml vs C 255.5 pg/ml; p < 0.05), PAR-2 (fIIPS 1807.9 pg/ml vs C 421.0 pg/ml; p < 0.05) and TGF-β1(fIIPS 283.0 pg/ml vs C 197.1 pg/ml; p < 0.01) in BALF in fIIPs versus C. The values of TNF-a in BALF did not differ significantly in fIIPs compared to controls. The ratios also showed differences in fIIPS and C: IL4Rα/TGF-β1 (fIIPS 6.19 vs C 0.68; p = 0.0143); TNF-α/IL4Rα (fIIPS 0.84 vs C 7.93; p = 0.043); TGF-β1/TNF-α (fIIPS 0.21 vs C 0.16; p = 0.0179) and protein/PAR-2 (fIIPS 0.06 vs C 0.28; p = 0.0033).Conclusions:We found that PAR-2, TGF-β1 and IL-4Rα are significantly up-regulated in the BALF of fIIPs compared to controls, therefore we suppose they could become biomarkers of fibroproliferative healing.

Interstitial Score and Concentrations of IL-4Rα, PAR-2, and MMP-7 in Bronchoalveolar Lavage Fluid Could Be Useful Markers for Distinguishing Idiopathic Interstitial Pneumonias

“…The positive correlation between IS and IL-4Rα supports our previous results, where we measured significantly higher concentrations of IL4-Rα in the BALF of patients with fIIP compared to controls [18]. IL-4Rα has been recognized as a key cytokine in the process of progressive fibrosis.…”

“…In our study, the concentrations of TNF-α in BALF were significantly lower in fIIP and CTD-ILD compared to HP. According to our previous [18,43] and present studies, we suggested that TNF-α levels are indicative of lung tissue inflammation, especially in the early phases of HP, rather than fibroproliferation. On the other hand, chronic stages of HP are characterized by more pronounced fibroproliferation rather than inflammation or granuloma formation, which is represented by an overexpression of IL-4Rα, as we previously described [44].…”

“…We calculated the ratios of biomarkers similarly to previous studies [ 18 , 46 , 54 ] where they showed, in contrast with the single biomarker levels, statistically significant differences. We assumed this approach might better reflect different pathologies because they help to balance the disturbances in volume of retrieved BALF.…”

“…Under pathologic conditions, AMs express different chemokines and cytokines, which are involved in inflammation and fibrosis [ 17 ]. In IIPs, AMs are the key cells responsible for inducing fibroproliferative healing [ 18 ].…”

“…Tumor necrosis factor (TNF)-α is one of the cytokines produced by AMs in human lungs [ 18 ]. This pro-inflammatory cytokine is released right after trauma or infection and plays a pivotal role in orchestrating the production of the pro-inflammatory cytokine cascade, which is why it is also called the “master regulator” [ 19 ].…”