Mesenchyme-derived inflammation during the saccular stage recruits macrophages and alters lung development

Benjamin C. Crawford; Jessica Chauviere Lee; Bertha C. Elias; Shivangi Dave; Riet van der Meer; Wei Han; Alexandria L. Sharkey; David S. Nichols; Charles Shissias; Lauren Pate; Hayden Tan; Dawn C. Newcomb; Wei Shi; Lawrence S. Prince; Erin J. Plosa; Bradley W. Richmond; Timothy S. Blackwell; Susan H. Guttentag; John T. Benjamin

doi:10.1172/jci.insight.193625

¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

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¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

Find articles by Richmond, B. in: PubMed | Google Scholar

¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

Find articles by Blackwell, T. in: PubMed | Google Scholar

¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

Find articles by Guttentag, S. in: PubMed | Google Scholar |

¹Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, United States of America

²Department of Internal Medicine, Division of Critical Care and Pulmonary Me, University of Michigan Medical School, Ann Arbor, United States of America

³Department of Medicine, Division of Allergy, Pulmonary, and Critical Care M, Vanderbilt University Medical Center, Nashville, United States of America

⁴Department of Internal Medicine, Division of Pulmonary, Critical Care and S, University of Cincinnati College of Medicine, Cincinnati, United States of America

⁵Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, United States of America

Find articles by Benjamin, J. in: PubMed | Google Scholar

JCI Insight. https://doi.org/10.1172/jci.insight.193625.
Copyright © 2026, Crawford et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 2, 2026 - Version history

Fibroblasts in the lung mesenchyme produce growth factors and extracellular matrix components that guide formation of distal airspaces during the saccular stage of lung development. Inflammation in preterm infants disrupts this process, leading to bronchopulmonary dysplasia (BPD). To examine how mesenchymal inflammation contributes to BPD pathogenesis, we developed a transgenic mouse model (“IKKβ^Tbx4”) in which expression of activated human IκB kinase beta (IKKβ), an upstream activator of NF-κB, was induced in Tbx4 lung enhancer-positive mesenchymal cells during the saccular stage of lung development (postnatal day 0 [PN0] - PN5). Saccular stage IKKβ^Tbx4 mice exhibited a BPD-like phenotype with interstitial thickening and reduced distal airspaces at PN5, progressing to emphysematous enlargement of the distal lung at 2 mo of age. Mesenchymal NF-κB activity upregulated the chemokines CCL2 and CCL7, recruiting CCR2^pos monocyte-derived macrophages to the lung. Recruited macrophages disrupted the elastin scaffold and impaired microvascular organization with reductions in CAP2 endothelial cells (aCaps) and pericytes. Blocking CCR2-dependent monocyte recruitment with a small molecule CCR2 antagonist rescued the abnormal lung phenotype. These findings identify mesenchyme-macrophage crosstalk as a mechanism by which inflammation disrupts saccular stage lung development, suggesting a role for this signaling axis in BPD pathogenesis.

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Mesenchyme-derived inflammation during the saccular stage recruits macrophages and alters lung development

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