Macrophages as determinants and regulators of systemic sclerosis-related interstitial lung disease.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38937794", "kind": "science-record", "revision": 3, "content_hash": "sha256:5e256c0cf7df36e155ef6162f999d9bd1f9d70ac7a9bf2ede65b65340d4bdcf5", "created_at": "2026-11-01T20:29:00Z", "updated_at": "2026-11-01T22:12:09Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Macrophages as determinants and regulators of systemic sclerosis-related interstitial lung disease.", "doi": "10.1186/s12967-024-05403-4", "pmid": "38937794", "authors": ["Shih-Ching Lee", "Chen-Hao Huang", "Yen-Jen Oyang", "Hsuan-Cheng Huang", "Hsueh-Fen Juan"], "journal": "Journal of translational medicine", "year": 2024, "abstract": "BACKGROUND: Interstitial lung disease (ILD) is the primary cause of mortality in systemic sclerosis (SSc), an autoimmune disease characterized by tissue fibrosis. SSc-related ILD (SSc-ILD) occurs more frequently in females aged 30-55 years, whereas idiopathic pulmonary fibrosis (IPF) is more prevalent in males aged 60-75 years. SSc-ILD occurs earlier than IPF and progresses rapidly. FCN1, FABP4, and SPP1 macrophages are involved in the pathogenesis of lung fibrosis; SPP1 macrophages demonstrate upregulated expression in both SSc-ILD and IPF. To identify the differences between SSc-ILD and IPF using single-cell analysis, clarify their distinct pathogeneses, and propose directions for prevention and treatment.\nMETHODS: We performed single-cell RNA sequencing on NCBI Gene Expression Omnibus (GEO) databases GSE159354 and GSE212109, and analyzed lung tissue samples across healthy controls, IPF, and SSc-ILD. The primary measures were the filtered genes integrated with batch correction and annotated cell types for distinguishing patients with SSc-ILD from healthy controls. We proposed an SSc-ILD pathogenesis using cell-cell interaction inferences, and predicted transcription factors regulating target genes using SCENIC. Drug target prediction of the TF gene was performed using Drug Bank Online.\nRESULTS: A subset of macrophages activates the MAPK signaling pathway under oxidative stress. Owing to the lack of inhibitory feedback from ANNEXIN and the autoimmune characteristics, this leads to an earlier onset of lung fibrosis compared to IPF. During initial lung injury, fibroblasts begin to activate the IL6 pathway under the influence of SPP1 alveolar macrophages, but IL6 appears unrelated to other inflammatory and immune cells. This may explain why tocilizumab (an anti-IL6-receptor antibody) only preserves lung function in patients with early SSc-ILD. Finally, we identified BCLAF1 and NFE2L2 as influencers of MAPK activation in macrophages. Metformin downregulates NFE2L2 and could serve as a repurposed drug candidate.\nCONCLUSIONS: SPP1 alveolar macrophages play a role in the profibrotic activity of IPF and SSc-ILD. However, SSc-ILD is influenced by autoimmunity and oxidative stress, leading to the continuous activation of MAPK in macrophages. This may result in an earlier onset of lung fibrosis than in IPF. Such differences could serve as potential research directions for early prevention and treatment.", "claims": [{"id": "claim-method", "statement": "All drugs tested and selected had the statistically highest score in the cluster of macrophages according to the Wilcoxon sum test, and p values were adjusted using the Benjamini–Hochberg method", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38937794", "locator": "sections[9] \"Drug-TF prediction and drug2cell\" paragraph 2", "quote": "All drugs tested and selected had the statistically highest score in the cluster of macrophages according to the Wilcoxon sum test, and p values were adjusted using the Benjamini–Hochberg method"}], "state": "complete"}, {"id": "claim-data-access", "statement": "The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38937794", "locator": "sections[25] \"Data availability\" paragraph 2", "quote": "The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:38937794"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE159354"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "blocked", "blocked_on": "method:group_comparison_wilcoxon", "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE159354"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:run_analysis blocked on method:group_comparison_wilcoxon"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:38937794", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s12967-024-05403-4", "sha256": "sha256:4b590d52954e2ed8ba9bee98dfae1a7ea734bd864f14f129d17f8b63c622b6f9", "bytes": 44352, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s12967-024-05403-4", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC11212242", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE159354", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159354", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE159354", "version": null, "note": "The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM4827158", "GSM4827159", "GSM4827160", "GSM4827161", "GSM4827162", "GSM4827163", "GSM4827164", "GSM4827165", "GSM4827166", "GSM4827167", "GSM4827168", "GSM4827169", "GSM4827170", "GSM4827171", "GSM4827172", "GSM4827173", "GSM4827174", "GSM4827175", "GSM4827176", "GSM4827177", "GSM4827178", "GSM4827179", "GSM4827180", "GSM4827181", "GSM4827182", "GSM4827183", "GSM4827184", "GSM4827185", "GSM4827186", "GSM4827187", "GSM4827188", "GSM4827189", "GSM4827190", "GSM4827191", "GSM4827192", "GSM4827193", "GSM4827194", "GSM4827195", "GSM4827196", "GSM4827197", "GSM4827198", "GSM4827199", "GSM4827200", "GSM4827201", "GSM4827202", "GSM4827203", "GSM4827204", "GSM4827205"], "sample_count": 48, "group_sizes": null, "group_sizes_basis": null, "platform": "20301", "taxon": "Homo sapiens", "title": "Single-cell RNA-seq of sort human lung explants from IPF and SSc-ILD patients", "resolution_checked_at": "2026-11-01T20:16:08Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE212109", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE212109", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE212109", "version": null, "note": "The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM6509487", "GSM6509488", "GSM6509489", "GSM6509490", "GSM6509491", "GSM6509492", "GSM6509493", "GSM6509494", "GSM6509495", "GSM6509496", "GSM6509497", "GSM6509498", "GSM6509499", "GSM6509500", "GSM6509501", "GSM6509502", "GSM6509503"], "sample_count": 17, "group_sizes": null, "group_sizes_basis": null, "platform": "24676", "taxon": "Homo sapiens", "title": "Epigenetic regulation of profibrotic macrophages in systemic sclerosis- associated interstitial lung disease", "resolution_checked_at": "2026-11-01T20:16:08Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE159354 not downloaded", "asset:data:geo:GSE159354 licence not read", "asset:data:geo:GSE212109 not downloaded", "asset:data:geo:GSE212109 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "group_comparison", "specific": "wilcoxon", "label": "Group comparison", "dsl_operations": [], "missing_operations": ["group_comparison_wilcoxon"], "expressible": false, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "All drugs tested and selected had the statistically highest score in the cluster of macrophages according to the Wilcoxon sum test, and p values were adjusted using the Benjamini–Hochberg method"}}], "targets": [], "gaps": ["method.group_comparison_wilcoxon"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": false, "required_operations": [], "missing_operations": ["group_comparison_wilcoxon"], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: wilcoxon."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE159354", "GSE212109"], "resolved_accessions": ["GSE159354", "GSE212109"], "statements": ["The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials."], "basis": "The paper names GSE159354, GSE212109 in NCBI Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": [], "assets": ["source:pmid:38937794", "data:geo:GSE159354"], "steps": []}, "must_build": {"dsl_operations": [{"operation": "group_comparison_wilcoxon", "unlocks_papers": null, "priority": null}], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE159354"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:22:38Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 13266, "completion_tokens": 910, "cached_tokens": 128}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:38937794", "type": "paper", "label": "pmid:38937794"}, {"id": "source:pmid:38937794", "type": "manuscript", "label": "PMID 38937794 full text"}, {"id": "data:geo:GSE159354", "type": "dataset", "label": "GEO GSE159354"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:38937794", "type": "paper", "label": "pmid:38937794"}, {"id": "source:pmid:38937794", "type": "manuscript", "label": "PMID 38937794 full text"}, {"id": "data:geo:GSE159354", "type": "dataset", "label": "GEO GSE159354"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-38937794", "type": "extraction", "used": ["source:pmid:38937794"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE159354", "type": "accession_resolution", "used": ["data:geo:GSE159354"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:38937794", "parent_hash": "sha256:da68a452b585476bcb9ee51fa65f417d09babd3ed344d9111552219a0af84d2e", "fork_of": null, "generation": 2}, "gaps": ["asset:data:geo:GSE159354 licence not read", "asset:data:geo:GSE159354 not downloaded", "asset:data:geo:GSE212109 licence not read", "asset:data:geo:GSE212109 not downloaded", "execution.not_run", "method.group_comparison_wilcoxon", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:run_analysis blocked on method:group_comparison_wilcoxon"], "assays": [{"role": "data_generation", "definition_id": "scrna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "unsupported", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["vention and treatment. METHODS: We performed single-cell RNA sequencing on NCBI Gene Expression Omnibus (GEO) databa", "udy design and analysis. B–F Overview of the scRNAseq landscape of GSE159354. Markers were used to", "patients, and three HCs from GSE159354 using scRNA-seq analysis (Fig. 1A). The filtered genes were"], "order_basis": "paper_text_order:795", "id": "assay:1"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["treatment. METHODS: We performed single-cell RNA sequencing on NCBI Gene Expression Omnibus (GEO) databa", "in both groups (Fig. 1C and D). Single-cell RNA-sequencing analysis of lung samples from sysetmic scler"], "order_basis": "paper_text_order:807", "id": "assay:2"}, {"role": "data_generation", "definition_id": "clinical_cohort", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["and annotated cell types for distinguishing patients with SSc-ILD from healthy controls. We proposed a", "or antibody) only preserves lung function in patients with early SSc-ILD. Finally, we identified BCLAF1", "analysis We analyzed lung samples from four patients with IPF, three patients with SSc-ILD patients, a", "g samples from four patients with IPF, three patients with SSc-ILD patients, and three HCs from GSE1593"], "order_basis": "paper_text_order:1094", "id": "assay:3"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["All drugs tested and selected had the statistically highest score in the cluster of macrophages according to the Wilcoxon sum test, and p values were adjusted using the Benjamini–Hochberg method"], "order_basis": "consumes_earlier_output", "id": "assay:4"}]}