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Markers of neutrophil degranulation in the lung microenvironment linked to idiopathic pulmonary fibrosis severity and survival

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) leads to progressive loss of lung function and mortality. Understanding mechanisms and markers of lung injury in IPF is paramount to improving outcomes for these patients. Despite the lack of systemic involvement in IPF, many analyses focus on identifying circulating prognostic markers. Using a proteomic discovery method followed by ELISA confirmation in multiple cohorts we explored novel markers of IPF survival in bronchoalveolar lavage fluid (BALF)

INSTRUMENT(S): Orbitrap Ascend

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Scott Matson

PROVIDER: MSV000098032 | MassIVE | Thu May 29 07:20:00 BST 2025

SECONDARY ACCESSION(S): PXD064413

REPOSITORIES: MassIVE

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Neutrophil degranulation in the lung microenvironment linked to idiopathic pulmonary fibrosis severity and survival.

Matson Scott M SM Ngo Linh T LT Sugawara Yui Y Fernando Veani V Lugo Claudia C Kaczorowski-Worthley Angela A Azeem Imaan I Harrison Alexis A Alsup Alex A Schueddig Emily E Koestler Devin D Rekowski Michaella J MJ Wolters Paul J PJ Lee Joyce S JS Washburn Michael P MP Solomon Joshua J JJ Demoruelle M Kristen MK

iScience 20251119 1

Idiopathic pulmonary fibrosis (IPF) causes progressive respiratory failure with variable survival trajectories among patients. Neutrophils accumulate in IPF lungs, but their mechanistic contribution to disease progression remains to be determined. We applied label-free quantitative proteomics to IPF lung tissue (<i>n</i> = 10) and bronchoalveolar lavage fluid (BALF) (<i>n</i> = 50) from patients with distinct survival outcomes. Neutrophil degranulation emerged as the pathway most strongly associ ...[more]

PMID: 41531731

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Proteome characterization of BALF extracellular vesicles in Idiopathic Pulmonary Fibrosis: unveiling undercover molecular pathways.

Project description:In the longtime challenge of identifying specific, easily-detectable and reliable biomarkers of interstitial lung diseases (ILDs), alternative biofluids, such as bronchoalveolar lavage fluid (BALF), have been extensively studied. In particular, BALF proteomics is gaining momentum and providing interesting new insights into the pathogenesis of ILDs, especially Idiopathic Pulmonary Fibrosis (IPF). Interest in the role of extracellular vesicles (EVs) in the pathogenesis of IPF has also grown. Though few, current studies on EVs in BALF of IPF patients focus mainly on miRNAs. To the best of our knowledge, the present study is therefore the first shotgun proteomic investigation of EVs isolated from BALF of IPF patients. Our main aim was to characterize the proteome of the vesicular component of BALF and to explore its individual impact on the pathogenesis of IPF. To this purpose, ultracentrifugation was chosen as EVs isolation technique and their purification was assessed by TEM, 2DE and LC-MS/MS. Our 2DE data and scatter plots showed considerable differences between the proteome of EVs and that of its supernatant and of whole BALF. Analysis of protein content and protein functions evidenced that EV proteins are predominantly involved in cytoskeleton remodeling, adenosine signaling, adrenergic signaling, C-peptide signaling and lipid metabolism. Our findings may suggest a wider system involvement in the disease pathogenesis and support the importance of pre-fractioning of complex samples, like BALF, in order to let low-abundant proteins-mediated pathways to emerge.

2021-08-06 | PXD025590 | Pride

Proteomic profiling of bronchoalveolar lavage fluid uncovers unique protein clusters linked to survival in idiopathic pulmonary fibrosis and interstitial pneumonia with autoimmune features

Project description:This study aimed to delineate molecular phenotypes of the lung microenvironment across idiopathic interestitial pneumonias, namely interstitial pneumonia with autoimmune features (IPAF)and idiopathic pulmonary fibrosis (IPF) through proteomic analysis of bronchoalveolar lavage fluid (BALF).

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Project description:The pathogenesis of idiopathic pulmonary fibrosis is multifactorial and characterized by progressive fibrosis and excessive accumulation of extracellular matrix in the interstitium of the lung, and driven by an imbalance between anti-fibrotic and pro-fibrotic factors leading to collagen deposition. In the present study we wanted to identify proteins involved in these processes, and performed high-resolution proteomic profiling of bronchoalveolar lavage (BAL) from IPF patients and controls. The proteomic analysis of BAL demonstrated that the complement system was highly differentially regulated in IPF patients as compared with controls.

2023-07-31 | PXD036638 | Pride

Quantitative proteomic analysis of bronchoalveolar lavage fluid in West Highland white terriers with canine idiopathic pulmonary fibrosis C4PR_LIV

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2022-05-20 | PXD028916 | Pride

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Project description:Patients affected by idiopathic pulmonary fibrosis (IPF), a progressive chronic and eventually fatal lung disease with unknown causes, suffer from delayed diagnosis due to the lack of predictive markers for disease development. Prior studies focused on the cellular and transcriptomic changes found in lung tissue during established, often terminal, lung disease. In clinical routine, bronchoscopy is applied for diagnosis and staging of suspected IPF affected individuals, thus providing us with a clinically applicable window, to study the cellular and transcriptional changes within affected individuals. Here we study a patient collective consisting of 11 IPF affected individuals and 11 healthy controls. We investigate their single cell transcriptomic profile alongside their cellular surface phenotype of alveolar-resident immune cells. Single cell transcriptional analysis reveals early accumulation of SPP1+ macrophages (SPP1+M) within the alveolar space as an early cellular sign of IPF, in the absence of a decline in lung function. Early-stage IPF accumulated SPP1+M were characterized by high expression of lipid storage and handling genes, accumulation of intracellular cholesterol and expression of proinflammatory cytokine expression. In silico developmental trajectory analysis revealed that SPP1+M are likely derived from monocytes. Finally to confirm the clinical diagnostic value of SPP1+ M we developed a flow cytometry panel to rapidly identify and test for the presence of SPP1+ M in bronchoalveolar lavage samples and confirm our observation in an independent validation cohort. Taken together, we show that SPP1+ M are associated with early IPF pathogenesis in the absence of an obvious decline in lung function, thus providing a clinically valuable markers for easy diagnosis of early IPF in clinical practice.

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Developmental programming in Idiopathic pulmonary fibrosis (IPF)

Project description:Global mRNA expression was compared between stable and progressive IPF using bronchoalveolar lavage derived mesenchymal stromal cells

2017-01-10 | GSE73854 | GEO

Fibroblast-derived extracellular vesicles contain SFRP1 and mediate pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disease characterized by aberrant intercellular communication, extracellular matrix deposition and destruction of functional lung tissue. While extracellular vesicles (EVs) accumulate in the IPF lung, their cargo and biological effects remain unclear. We interrogated the proteome of EV and non-EV fractions during pulmonary fibrosis and characterize their contribution to fibrosis. EVs accumulated 14 days post-bleomycin challenge, correlating with decreased lung function and initiated fibrogenesis in healthy precision-cut lung slices. Label-free proteomics of broncho-alveolar lavage fluid (BALF)-EVs collected from mice challenged with bleomycin or control identified 107 proteins enriched in fibrotic vesicles. Multiomic analysis revealed fibroblasts as a major cellular source of BALF-EV cargo, which was enriched in Secreted Frizzled Related Protein 1 (SFRP1). Sfrp1 deficiency inhibited the activity of fibroblast-derived EVs to potentiate lung fibrosis in vivo. SFRP1 led to increased transitional cell markers, such as Krt8, and WNT/β-catenin signaling in primary alveolar type 2 cells. SFRP1 is expressed within the IPF lung and localized at the surface of EVs from patient-derived fibroblasts and BALF. Our work reveals altered EV protein cargo in fibrotic EVs promoting fibrogenesis and identifies fibroblast derived vesicular SFRP1 as fibrotic mediator and potential therapeutic target for IPF.

2024-11-05 | GSE272679 | GEO

Serial Analysis of Gene Expression molecular signature for disease progression in Idiopathic Pulmonary Fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrosing interstitial lung disease that is unresponsive to current therapy. While it carries a median survival of less than 3 years its rate of progression varies widely between patients. We hypothesized that studying the gene expression profiles of physiologically stable patients and those in which the disease progressed rapidly after the initial diagnosis would aid in the search for biomarkers and contribute to the understanding of disease pathogenesis. We generated 12 Idiopathic Pulmonary Fibrosis (IPF) lung parenchyma SAGE profiles. Initial cluster analysis including 8 other public available lung SAGE libraries verified that the IPF transcriptome is distinct from normal lung tissue and other lung diseases like COPD. In order to identify candidate markers of disease progression we segregated the IPF SAGE profiles in two groups based on clinical parameters regarding lung volume and lung function.

2009-04-07 | E-GEOD-11665 | biostudies-arrayexpress

Validated Gene Expression Signatures of Idiopathic Pulmonary Fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease that is difficult to diagnose and follows an unpredictable clinical course. The object of this study was to develop a predictive gene signature model of IPF from whole lung tissue. We collected whole lung samples from 11 IPF patients undergoing diagnostic surgical biopsy or transplantation. Whenever possible, samples were obtained from different lobes. Normals consisted of healthy organs donated for transplantation. We measured gene expression on microarrays. Data were analyzed by hierarchical clustering and Principal Component Analysis. By this approach, we found that gene expression was similar in the upper and lower lobes of individuals with IPF. We also found that biopsied and explanted specimens contained different patterns of gene expression; therefore, we analyzed biopsies and explants separately. Signatures were derived by fitting top genes to a Bayesian probit regression model. We developed a 153-gene signature that discriminates IPF biopsies from normal. We also developed a 70-gene signature that discriminates IPF explants from normal. Both signatures were validated on an independent cohort. The IPF Biopsy signature correctly diagnosed 76% of the validation cases (p < 0.01), while IPF Explant correctly diagnosed 78% (p < 0.001). Examination of differentially expressed genes revealed partial overlap between IPF Biopsy and IPF Explant and almost no overlap with previously reported IPF gene lists. However, several overlapping genes may provide a basis for developing therapeutic targets. 17 samples from 11 patients with IPF (6 patients provided a pair of samples from upper and lower lobes; 5 patients contributed singleton samples); 6 control specimens were obtained from routine lung volume reduction of healthy donor lungs at the time of lung transplantation.

2011-11-01 | E-GEOD-24206 | biostudies-arrayexpress

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