# Mesenchymal inflammatory signaling in regulation of the immune response and tissue dysfunction during lipopolysaccharide-induced acute lung injury

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $75,142

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by severe pulmonary
inflammation leading to alveolar injury, non-cardiogenic pulmonary edema, and impaired gas exchange often
necessitating mechanical ventilation. ARDS can be caused by direct or indirect injury to the lungs, with the
most common etiologies of injury being pneumonia, aspiration of gastric contents and sepsis. Despite
significant interest in finding new therapies for ARDS, treatment has remained predominately supportive,
highlighting the need for improved mechanistic understanding. The pulmonary mesenchyme resides in close
proximity to the alveolar epithelium, vascular endothelium, and resident and recruited immune cells, placing the
mesenchyme in an optimal position to synthesize and respond to signals from the microenvironment. In this
proposal we aim to elucidate how the pulmonary mesenchyme incorporates inflammatory signals to modify the
immune response and tissue injury in ARDS. The nuclear factor -B (NF-B) family of transcription factors are
activated downstream of several pattern-recognition and cytokine receptors, and play an important role in
mediating inflammatory responses. A20, encoded by Tnfaip3, is a negative regulator of NF-B, and has been
found in both immune and epithelial cells to play a crucial role in limiting excessive inflammation and tissue
injury. The intranasal delivery of bacterial lipopolysaccharide (LPS) is a well-accepted murine model for ARDS,
and LPS is known to activate NF-B through the pattern-recognition receptor Toll-like receptor 4 (TLR4).
Preliminary data from our lab shows that in response to LPS, lung fibroblasts in which Tnfaip3 has been
deleted have increased expression of both chemokines and cytokines known to recruit immune cells and alter
vascular permeability, both physiologically important aspects of ARDS pathogenesis. We hypothesize that
impaired negative regulation of mesenchymal NF-B signaling in ARDS leads to increased pulmonary
recruitment of immune cells and physiologic injury, and propose experiments to test this hypothesis. Answering
these questions will lead to important insight into the role of the lung mesenchyme in mediating the
pathophysiology of ARDS. We hope that the fundamental knowledge gained with these studies will eventually
contribute to the development of more targeted therapeutics for this devastating disease. The above
experimental proposal is part of a comprehensive training plan that I have built with my mentors to develop the
skills and knowledge needed to become a successful independent investigator in the field of lung biology, with
an emphasis on acute lung injury/ARDS. As a unique part of this plan I have assembled a Career Development
Committee composed of physician-scientists from the fields of pulmonology and immunology who will serve as
both scientific and career advisors. Upon completion of the proposed training plan with the suppor...

## Key facts

- **NIH application ID:** 10389796
- **Project number:** 1F32HL156452-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Nancy Christine Allen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $75,142
- **Award type:** 1
- **Project period:** 2022-03-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389796

## Citation

> US National Institutes of Health, RePORTER application 10389796, Mesenchymal inflammatory signaling in regulation of the immune response and tissue dysfunction during lipopolysaccharide-induced acute lung injury (1F32HL156452-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10389796. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*