# Molecular control of lung endothelial barrier function in ALI

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $386,250

## Abstract

PROJECT SUMMARY
ALI/ARDS is a serious condition with high mortality rates, and more complete understanding of pathologic
mechanisms mediating lung vascular inflammation and barrier dysfunction in ARDS is critical for development
of efficient therapeutic approaches to confront this devastating disease. Previous studies by our and other
groups revealed pronounced anti-inflammatory and barrier enhancing effects of cyclic AMP elevating agonists
on pulmonary vascular endothelium, which accelerated ALI recovery. Endogenous cAMP levels also appear to
be critical for the maintenance of endothelial cell anti-inflammatory status and barrier function. However, septic
and ALI conditions lead to impairment of cAMP homeostasis, which may contribute to severity of endothelial
dysfunction and lung injury in ARDS. The importance of this mechanism is supported by beneficial effects of
pharmacological inhibition of cAMP hydrolyzing enzyme, phosphodiesterase (PDE) in preclinical models of
septic ALI. Despite these encouraging results, precise molecular mechanisms of PDE activation in
inflammatory conditions still remain to be elucidated.
 Coagulation and inflammation are activated by the same types of challenges and correlate both
temporally and spatially in different pathologies, but mechanistic interactions between these two processes are
incompletely understood. Fibrinogen is a key component of the coagulation system. Increased levels of
fibrinogen and fibrin deposition are distinctive features of advanced ALI and septic syndromes. Fibrinogen
directly interacts with α5β1 integrin adhesion receptor expressed by pulmonary endothelial cells. Our exciting
pilot studies show that this interaction may augment EC inflammation and barrier dysfunction caused by
bacterial pathogens via recruitment of PDE4 to the α5-integrin associated signaling protein complex. This
proposal will investigate for the first time the molecular mechanism of synergy between ARDS-relevant
coagulation component fibrinogen and lung EC inflammation caused by bacterial particles.
 Aim-1 will employ in vitro and in vivo models of ALI caused by Gram-positive bacterial particles to
evaluate fibrinogen role in lung vascular endothelial dysfunction and severity of lung injury. Aim-2 will
investigate assembly and activation of α5-integrin-ILK-paxillin signalosome and evaluate its role in the
mediation of fibrinogen-induced exacerbation of endothelial dysfunction and lung inflammation. Aim-3 will study
targeting of PDE4 to fibrinogen-activated α5-integrin-ILK-paxillin signalosome and its significance for PDE4-
dependent suppression of intracellular cAMP and augmentation of HKSA-induced ALI.

## Key facts

- **NIH application ID:** 9916818
- **Project number:** 5R01HL087823-12
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Konstantin Birukov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2008-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916818

## Citation

> US National Institutes of Health, RePORTER application 9916818, Molecular control of lung endothelial barrier function in ALI (5R01HL087823-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9916818. Licensed CC0.

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