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This work was supported by the Foundation for the National Institutes of Health Grants 1 U01 1U01HL145550 and 5R01HL123766-04. D.A.A.V. was supported by Foundation for the National Institutes of Health Grant P50CA097190. T.C. received the support of a fellowship from La Caixa Foundation (LCF/BQ/PI22/11910042). P.A.G. was supported by Foundation for the National Institutes of Health Grant 7F32CA261023-03. This project used the UPCI Cancer Biomarkers Facility: Luminex Core Laboratory, which was supported by Award P30CA047904.

Analysis of institutional authors

Cruz, TamaraAuthor

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March 18, 2024
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End-Stage Idiopathic Pulmonary Fibrosis Lung Microenvironment Promotes Impaired NK Activity

Publicated to:Journal Of Immunology. 211 (7): 1073-1081 - 2023-10-01 211(7), DOI: 10.4049/jimmunol.2300182

Authors: Cruz, T; Garcia, PAA; Chamucero-Millares, JA; Bondonese, A; Mitash, N; Sembrat, J; Tabib, T; Zhang, WP; Seyed, N; Peters, V; Stacey, S; Vignali, D; Mora, AL; Lafyatis, R; Rojas, M

Affiliations

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; Tumor Microenvironment Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, U - Author
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA. - Author
Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University, Columbus, OH. - Author
Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University, Columbus, OH.; Comprehensive Transplant Center, Division of Transplant Surgery, The Ohio State University, Columbus, OH.; The Davis Heart and Lung Research Institute at The - Author
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA. - Author
Fundacio Clinic per a la Recerca Biomedica, IDIBAPS, 08036 Barcelona, Spain. - Author
IDIBAPS, Fdn Clin Recerca Biomed, Barcelona 08036, Spain - Author
Ohio State Univ, Davis Heart & Lung Res Inst, Coll Med, Wexner Med, Columbus, OH USA - Author
Ohio State Univ, Div Pulm Crit Care & Sleep Med, Columbus, OH USA - Author
Ohio State Univ, Div Transplant Surg, Comprehens Transplant Ctr, Columbus, OH USA - Author
Univ Pittsburgh, Canc Immunol & Immunotherapy Program, UPMC Hillman Canc Ctr, Sch Med, Pittsburgh, PA USA - Author
Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA - Author
Univ Pittsburgh, Div Pulm Allergy & Crit Care, Sch Med, Pittsburgh, PA USA - Author
Univ Pittsburgh, Div Rheumatol & Clin Immunol, Sch Med, Pittsburgh, PA USA - Author
Univ Pittsburgh, Tumor MicroenvironmCtr, Sch Med, Pittsburgh, PA USA - Author
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fibrotic age-related chronic lung disease characterized by the accumulation of senescent cells. Whether impaired immune response is responsible for the accumulation of senescent cells in the IPF lung remains unknown. In this study, we characterized the NK phenotype in IPF lungs via flow cytometry using 5-dodecanoylaminofluorescein di-beta-D-galactopyranoside, markers of tissue residence, and chemokine receptors. The effect of the lung microenvironment was evaluated using lung fibroblast (LF) conditioned media (CM), and the bleomycin-induced pulmonary fibrosis mouse model was used to assess the in vivo relationship between NK cells and the accumulation of senescent cells. We found that NK cells from the lower lobe of IPF patients exhibited immune-senescent and impaired CD57(-)NKG2A(+) phenotype. We also observed that culture of NK cells from healthy donors in CM from IPF lower lobe lung fibroblasts induced a senescent-like phenotype and impaired cytotoxic capacity. There is an impaired NK recruitment by LF, and NKs presented decreased migration toward their CM. In addition, NK cell-depleted mice treated with bleomycin showed increased collagen deposition and accumulation of different populations of senescent cells compared with controls. The IPF lung microenvironment induces a dysfunctional NK phenotype limiting the clearance of lung senescent cells and the resolution of lung fibrosis. We propose that impaired NK activity could be one of the mechanisms responsible for perpetuating the accumulation of senescent cells in IPF lungs.

Keywords

chemokinesexpressionnatural-killer-cellsperipheral-bloodsenescence5 dodecanoylaminofluorescein di beta dextro galactopyranosideActivated stellate cellsAdultAnimalAnimal cellAnimalsAntineoplastic agentAntineoplastic agentsArticleBioaccumulationBleomycinBleomycin-induced pulmonary fibrosisCd57 antigenCell activityCell agingCell cultureCell isolationCell migrationCell migration assayCell populationChemokine receptorClinical articleClinical assessmentClinical evaluationCollagenControlled studyCytotoxicityCytotoxicity assayDisease courseFemaleFibroblastFibroblastsFibrosing alveolitisFibrosisFlow cytometryGene expressionHealth promotionHumanIdiopathic pulmonary fibrosisIn vivo studyLactate dehydrogenaseLungLung fibroblastMaleMiceMicroenvironmentMouseNatural killer cellNatural killer cell receptor nkg2aNonhumanPathologyPhenotypePyranosideReal time polymerase chain reactionSample sizeTranscriptomicsUnclassified drug

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of Immunology due to its progression and the good impact it has achieved in recent years, according to the agency Scopus (SJR), it has become a reference in its field. In the year of publication of the work, 2023, it was in position , thus managing to position itself as a Q1 (Primer Cuartil), in the category Immunology and Allergy.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.21. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 3.63 (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-03, the following number of citations:

  • WoS: 7
  • Scopus: 5
  • Europe PMC: 3

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-03:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 9.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 11 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 4.25.
  • The number of mentions on the social network X (formerly Twitter): 2 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Cruz Santa Cruz, Tamara) .