Airway fibrin formation cascade in allergic asthma exacerbation: implications for inflammation and remodeling

Abstract

Background Airway remodeling in patients with asthma, which leads to a decline in pulmonary function, is likely the result of repeated exacerbations often provoked by aeroallergen exposures. Aeroallegen exposure triggers a stereotypic response orchestrated by growth factor cytokines and other protein mediators. This results in a late-phase allergic reaction characterized by vascular permeability, recruitment of activated leukocytes, and activation of structural cells of the airway. The spectrum of protein mediators and their functions are incompletely understood. Methods Bronchoalveolar lavage fluid (BALF) samples were obtained from 12 volunteers who exhibited robust eosinophilic recruitment following segmental bronchial provocation with allergen (SBP-Ag). We systematically identified and quantified proteins in BALF using high-performance liquid chromatography–high-resolution mass spectrometry (LC–MS/MS) followed by pathway analysis and correlations with airway physiology. Results Pairwise analysis of protein abundance in BALF pre- vs post-SBP-Ag revealed that 55 proteins were upregulated and 103 proteins were downregulated. We observed enrichment of groups of proteins mapping to hemostasis/fibrin clot, platelet activation, lipoprotein assembly, neutrophil degranulation proteins, and acute-phase inflammation-airway remodeling pathways. The abundances of F2 and Fibrinogen γ (FGG) correlated with eosinophil numbers, whereas SERPINA3 negatively correlated with change in FeNO. The coagulation proteins F2 and KNG negatively correlated with FN1 an index of airway remodeling. Interestingly, patients with lower FEV1 showed distinct allergen-induced patterns of 8 BALF proteins, including MUC1, alarmins (HSPB1), and actin polymerization factors. Conclusions Protein abundance of the fibrin formation cascade, platelet activation and remodeling are associated with late-phase leukocyte numbers and markers of remodeling. Patients with lower FEV1 have distinct dynamic responses to allergen.

Identification of Emerging Drug Targets for Pulmonary Functions Through Mendelian Randomization Analysis of the Plasma Proteome

“…[31,32] Fibronectin-1 (FN1) signi cantly affects asthma by aiding airway remodeling and enhancing in ammatory cell activity and brosis. [33] After allergen exposure, the production of FN1, particularly its extra domain A (ED-A) variant, is associated with signi cant structural alterations in the airways, leading to reduced lung function. [34] This relationship highlights FN1 as a possible target for asthma treatments aiming to enhance lung function metrics.…”

A Preliminary Study in Immune Response of BALB/c and C57BL/6 Mice with a Locally Allergic Rhinitis Model

“…The top 10 core genes which are most different between the two mice strain were Kng2, Kng1, Gnb3, Lpar3, Lpar1, Pik3r1, Pf4, Apob, Rps9, and Fbxo2. Recently Zhu et al found that Kng was negatively correlated with airway remodeling in human asthma, 34 Pik3r1 is an essential component of the PI3Kδ pathway, associated with immune system defects and dysregulation. 35 Athina et al demonstrated that reduced Apob in AR patients leads to decreased antioxidant capacity and impaired ability to inhibit monoclonal factor-κB expression and pro-inflammatory cytokine secretion.…”

Next steps in precision approaches for asthma-proteomics and asthma endotypes

“…For example, applications of proteomics to asthmatics after provocation using segmental allergen challenge or naturally induced exacerbations will be more robust for identifying activated pathways driving disease. Studies conducted since the publication of this review using paired segmental allergen challenge coupled with invasive BAL sampling show the presence of allergen-elicited fibrin cascade ( 6 ). An important observation from this work is that markedly diverse protein patterns are present during the exacerbation than what could be identified by analysis of stable disease.…”