Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates

Andrea Toth, Shelby Steinmeyer, Paranthaman Kannan, Jerilyn Gray, Courtney M. Jackson, Shibabrata Mukherjee, Martin Demmert, Joshua R. Sheak, Daniel Benson, Joe Kitzmiller, Joseph A. Wayman, Pietro Presicce, Christopher Cates, Rhea Rubin, Kashish Chetal, Yina Du, Yifei Miao, Mingxia Gu, Minzhe Guo, Vladimir V. Kalinichenko, Suhas G. Kallapur, Emily R. Miraldi, Yan Xu, Daniel Swarr, Ian Lewkowich, Nathan Salomonis, Lisa Miller, Jennifer S. Sucre, Jeffrey A. Whitsett, Claire A. Chougnet, Alan H. Job, Hitesh Deshmukh, William J. Zacharias

Preprint posted on June 25, 2021

Monkey Business. Toth, Steinmeyer and colleagues develop a pre-natal primate model of lung inflammation to study the molecular events of mammalian alveologenesis.

Selected by Sagar Varankar

Categories: developmental biology


Lung development proceeds through a complex array of morphogenic processes to generate the branching airways and gas exchange surface of the alveoli1. During childbirth, alveolar spaces undergo a dramatic fluid-to-gas displacement to facilitate respiration. These processes involve a crosstalk between multiple cell compartments and their accurate anatomical positioning to ensure organ function2,3. However, disruptions in these systems can cause neonatal respiratory distress which is fatal without appropriate clinical interventions. Impaired alveologenesis, which can stem from an inflammatory in utero environment, is often associated with chronic lung disease of prematurity (CLDP) or bronchopulmonary dysplasia (BPD) in pre-mature neonates4,5. While current therapies can reduce the mortality and morbidity associated with these conditions, several individuals experience persistent tissue injury and increased risks to respiratory disorders later in life.

Murine models of development, homeostasis and disease have allowed us to understand several aspects of mammalian pulmonary biology. However, due to inherent differences in tissue architecture, cellular composition and developmental time frames, several observations from mice have not been effectively translated into the human settings6. These have necessitated the investigation of non-murine animal models. Due to their evolutionary proximity, primates share several anatomical and developmental features with humans and may serve as improved pre-clinical models for pathological conditions.

In this preprint Toth, Steinmeyer and colleagues present the Rhesus macaque lung as a model to recapitulate the cellular and molecular events of alveologenesis. Parallels drawn with human datasets for development, cellular dynamics and response to injury highlight the clinical relevance of this system.

Key Findings:

Single cell atlas of the developing macaque lung:

The authors initiated this study by identifying time points during human and macaque gestation which coincide with gross developmental changes in the lung. They then performed single cell RNA sequencing with macaque lungs to understand the molecular events that drive and contribute to alveologenesis. Observations pertaining to cellular heterogeneity, transitional progenitors and proliferative states were captured for multiple cell populations which were comparable to previous observations from mouse and human datasets. Using statistically robust analytical tools (CellChat, Condiments, Slingshot) the authors identified, (i) an active role of alveolar type 1 (AT1) cells in capillary patterning, (ii) matrix fibroblasts as a signalling hub for the epithelium and (iii) the novel role of mesenchyme-derived endothelin in alveologenesis. Molecular and anatomical similarities with humans, thus posit the macaque lung as a clinically relevant model of mammalian pulmonary development.

LPS injury model of pulmonary development:

With improved insights on primate lung development, the authors evaluated the effect of lipopolysaccharide (LPS)-induced inflammation on alveologenesis. Several features of paediatric pulmonary disorders were recapitulated in response to LPS treatment including (i) a loss of regenerative cell populations, (ii) activation of matrix fibroblasts and (iii) the enrichment of inflammatory pathways. The authors further identified LPS-induced changes in the differentiation trajectories of epithelial and endothelial cells which were associated with alveolar simplification. These observations highlighted the suitability of primate models for understanding human lung developmental disorders.

Blocking the inflammatory milieu fosters tissue repair after LPS injury:

To investigate mechanisms of tissue repair, the authors targeted inflammatory pathways which were enriched in the LPS-treated macaque lungs. Anakinra, an interleukin-1 receptor (IL1R) antagonist, and adalimumab, an anti-tumour necrosis factor (TNF) monoclonal antibody, were selected as clinically-approved anti-inflammatory agents and administered to pregnant macaques prior to LPS treatment. While this resulted in a modest downregulation of the inflammatory signature, the cellular heterogeneity of the foetal lung and developmental pathways in the stroma were restored to pre-injury levels. These observations indicated a clinically relevant blockade of pre-natal inflammation which can promote alveolar maturation and potentially improve the outcome of paediatric pulmonary disorders.

Why I Chose This Preprint:

I found this pre-print exciting as it bridges the gap between mouse and human studies by establishing a primate model of lung development and injury. The authors recapitulate several features of human lung development with macaque lungs, including their response to inflammatory agents. In addition to its relevance in studying pulmonary development, this model can be leveraged to investigate a wide range of respiratory disorders and can eventually be extended to other organs. The insights derived from similar studies will hold great therapeutic value and improve the efficacy of clinical interventions.

Questions for the authors:

This preprint presents a clinically relevant model of lung development. Considering the complicated inter-cellular crosstalk and temporal activation of signalling cascades during development, my questions for the authors are as follows:

  1. The authors have used anti-inflammatory agents to promote repair after LPS-induced injury. As per the methods and experimental plans detailed in the pre-print, these agents were introduced prior to LPS administration. From a clinical perspective, would it be relevant to examine the effects of the inflammatory blockade after LPS exposure? Further, several studies have implicated inflammation as a developmentally crucial process. Would the inflammatory blockade perturb organogenesis or tissue morphogenesis at the organismal level if pregnancy were continued until birth?
  2. The authors have extensively examined the crosstalk between cellular compartments under different treatment conditions. It would be interesting to assess whether the injury or inflammatory blockade affected the ECM composition or stiffness of tissues? As anti-inflammatory agents can perturb the extracellular composition of multiple organs, the authors could examine for any developmental effects in the foetus following specific treatments.
  3. The single cell dataset generated in this pre-print is an exciting resource to understand primate lung biology. In addition to examining epithelial-endothelial and epithelial-stromal crosstalk, did the authors examine any intra-epithelial signalling that may contribute to alveologenesis?


  1. Lee, J. H. & Rawlins, E. L. Developmental mechanisms and adult stem cells for therapeutic lung regeneration. Dev. Biol. 433, 166–176 (2018).
  2. Jacob, A. et al. Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21, 472-488.e10 (2017).
  3. Morrisey, E. E. & Hogan, B. L. M. Preparing for the First Breath: Genetic and Cellular Mechanisms in Lung Development. Dev. Cell 18, 8–23 (2010).
  4. Thébaud, B. et al. Bronchopulmonary dysplasia. Nat. Rev. Dis. Prim. 5, (2019).
  5. Evans, D. A., Wilmott, R. W. & Whitsett, J. A. Surfactant replacement therapy for adult respiratory distress syndrome in children. Pediatr. Pulmonol. 21, 328–336 (1996).
  6. Basil, M. C. & Morrisey, E. E. Lung regeneration: a tale of mice and men. Semin. Cell Dev. Biol. 100, 88–100 (2020).


Posted on: 19th July 2021


Read preprint (2 votes)

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the developmental biology category:

2nd Conference of the Visegrád Group Society for Developmental Biology

Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)


List by Nándor Lipták


The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!


List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.


List by Alex Eve

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020


List by Jesus Victorino

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.


List by Alex Eve

Society for Developmental Biology 79th Annual Meeting

Preprints at SDB 2020


List by Irepan Salvador-Martinez, Martin Estermann

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020


List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.


List by Ana Dorrego-Rivas

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.


List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20


List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.


List by Paul Gerald L. Sanchez and Stefano Vianello

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)


List by Madhuja Samaddar et al.

EDBC Alicante 2019

Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.


List by Sergio Menchero et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019


List by Dey Lab

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.


List by Alex Eve

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.


List by Rob Hynds

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London


List by Alex Eve

Pattern formation during development

The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.


List by Alexa Sadier

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019


List by Dey Lab

Zebrafish immunology

A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.


List by Shikha Nayar