Evidence map›Paper›PMID 30333529›Full record

ArticleCell death & disease2018

Efferocytosis of apoptotic alveolar epithelial cells is sufficient to initiate lung fibrosis.

Kevin K Kim, Megan R Dotson, Manisha Agarwal, Jibing Yang, Patrick B Bradley, Natalia Subbotina, John J Osterholzer, Thomas H Sisson

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell death & disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed, 1 pooled it
3.8field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

52 citing papers in PubMed, 1 synthesis or guideline pooled it, 85 citations in OpenAlex.

  1. Pooled it
  2. Folate metabolism-related gene signature reveals prognostic and immunological characteristics in idiopathic pulmonary fibrosis.Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG · 2026
    Article
  3. Article
  4. Review
  5. Regulated Cell Death in Idiopathic Pulmonary Fibrosis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026
    Review
  6. Review
  7. Review
  8. Review
  9. Article
  10. Review
  11. Review
  12. Review
  13. Degradation of oxidized phospholipids by lysosomal phospholipase A2 regulates pulmonary fibrosis.American journal of physiology. Lung cellular and molecular physiology · 2025
    Article
  14. Review
  15. Article
  16. Review
  17. Pulmonary fibrosis: from mechanisms to therapies.Journal of translational medicine · 2025
    Review
  18. Review
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 1 institution in 1 country.

Kevin K KimDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA. kevkim@med.umich.edu.
Megan R DotsonDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Manisha AgarwalDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Jibing YangDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Patrick B BradleyDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Natalia SubbotinaDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
John J OsterholzerDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Thomas H SissonDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
University of Michigan–Ann Arbor · US

Funding

The Anti-protease and Vitronectin-binding Functions of PAI-1 in Lung FibrosisR01HL078871 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SISSON, THOMAS H · 2007 to 2018
$4.0M
Type I collagen signaling in lung injury and fibrosisR01HL108904 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KIM, KEVIN KEEWOUN · 2012 to 2020
$3.5M
BLRD VA I01 BX002120NHLBI NIH HHS R01 HL078871NHLBI NIH HHS R01 HL108904
6 · The paper itself

Abstract

Type II alveolar epithelial cell (AEC) apoptosis is a prominent feature of fibrotic lung diseases and animal models of pulmonary fibrosis. While there is growing recognition of the importance of AEC injury and apoptosis as a causal factor in fibrosis, the underlying mechanisms that link these processes remain unknown. We have previously shown that targeting the type II alveolar epithelium for injury by repetitively administering diphtheria toxin to transgenic mice expressing the diphtheria toxin receptor off of the surfactant protein C promoter (SPC-DTR) develop lung fibrosis, confirming that AEC injury is sufficient to cause fibrosis. In the present study, we find that SPC-DTR mice develop increased activation of caspase 3/7 after initiation of diphtheria toxin treatment consistent with apoptosis within AECs. We also find evidence of efferocytosis, the uptake of apoptotic cells, by alveolar macrophages in this model. To determine the importance of efferocytosis in lung fibrosis, we treated cultured alveolar macrophages with apoptotic type II AECs and found that the uptake induced pro-fibrotic gene expression. We also found that the repetitive intrapulmonary administration of apoptotic type II AEC or MLE-12 cells induces lung fibrosis. Finally, mice lacking a key efferocytosis receptor, CD36, developed attenuated fibrosis in response to apoptotic MLE-12 cells. Collectively, these studies support a novel mechanism linking AEC apoptosis with macrophage pro-fibrotic activation via efferocytosis and reveal previously unrecognized therapeutic targets.

Indexed as

PhagocytosisAlveolar Epithelial CellsAnimalsApoptosisBronchoalveolar Lavage FluidCaspase 3Caspase 7CD36 AntigensCell LineDiphtheria ToxinGene Expression RegulationHeparin-binding EGF-like Growth FactorHumansIntercellular Signaling Peptides and ProteinsMacrophage ActivationMacrophages, AlveolarCasp3 protein, mouseCasp7 protein, mouseCaspase 3Caspase 7CD36 AntigensDiphtheria ToxinHeparin-binding EGF-like Growth FactorIntercellular Signaling Peptides and ProteinsPulmonary Surfactant-Associated Protein CRecombinant Fusion ProteinsSftpc protein, mouse

Identifiers

PMID30333529
PMCPMC6193049
OpenAlexW2897027697

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.