# The Pulmonary Lymphatics in Inflammation and Disease

> **NIH NIH K01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $128,868

## Abstract

PROJECT SUMMARY/ABSTRACT 
Pulmonary lymphatic vessels are thought to be critical for lung function due to the vulnerability of the lungs to 
edema and their constant exposure to pathogens. Indeed, abnormal pulmonary lymphatics are seen in 
association with nearly every chronic lung disease including transplant rejection, pulmonary fibrosis, and 
emphysema, which combined affect nearly 32 million Americans. However, it remains unclear whether these 
abnormal lymphatics are a consequence of the disease or if lymphatic dysfunction is pathogenic, leaving 
potential therapeutic targets unexplored. This proposal addresses both an outstanding gap in our ability to study 
pulmonary lymphatic function and also investigates the basic role of lymphatics in lung disease using two novel 
mouse models of impaired pulmonary lymphatic flow. The first model uses Clec2-­mutant mice, which have 
severely impaired lymph flow due to an absent platelet plug at the lympho-­venous junction and retrograde flow 
of blood into the lymphatic system that prevents lymphatic drainage. In the second model, lung-­specific lymphatic 
deletion is achieved by inducing diphtheria toxin-­mediated cell death of lymphatic endothelial cells in mouse lung 
transplants. These models show that lymphatic dysfunction leads to accumulation of leukocytes and formation 
of lymphoid tissue in the lung parenchyma. Significantly, mice with impaired lymphatic flow also have alveolar
enlargement and lung injury that resembles human emphysema. In Aim 1 of this proposal, both models will be
used to investigate the role of pulmonary lymphatics in leukocyte trafficking and test whether lymphatic function 
plays a role in immune cell specification and the inflammatory milieu of the lung. Aim 2 will use pulmonary 
function tests, CT imaging, and expression studies to test the hypothesis that lymphatic dysfunction causes a 
spontaneous emphysema phenotype in mice, and will investigate the mechanism by which lymphatic dysfunction 
causes lung injury using rescue studies. These studies are predicted to provide in vivo models for understanding 
the interplay between lymphatic function, inflammation, and lung injury and may uncover an unappreciated role 
for lymphatics in emphysema. This proposal also plays a central role in a career development plan for becoming 
a successful independent investigator focused on vascular biology and disease. The training plan described here 
provides an opportunity to gain expertise in mouse modeling of human disease, transcriptomics, and physiologic 
and radiographic analysis of the mouse lung. The University of Pennsylvania is an ideal environment in which to 
execute this training plan not only because of its excellent physical resources, but also because of its intellectual 
community of researchers with a track record of strong mentorship of early stage investigators.

## Key facts

- **NIH application ID:** 10459252
- **Project number:** 5K01HL145365-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Hasina Outtz Reed
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $128,868
- **Award type:** 5
- **Project period:** 2019-07-23 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459252

## Citation

> US National Institutes of Health, RePORTER application 10459252, The Pulmonary Lymphatics in Inflammation and Disease (5K01HL145365-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10459252. Licensed CC0.

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