# Regulation of phosphodiesterases and cAMP signaling during the host-pathogen interaction in the pulmonary endothelium

> **NIH NIH R01** · UNIVERSITY OF SOUTH ALABAMA · 2020 · $378,245

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease associated with high
morbidity/mortality and limited treatment options. A breakdown of pulmonary endothelial barrier function,
leading to edema and impaired lung function, is a hallmark of ARDS. It is well established that stimulation of
cAMP synthesis, such as with β-adrenoceptor agonists, enhances endothelial barrier function and is protective
in preclinical models of sterile lung injury such as upon LPS administration. However, clinical trials probing the
utility of β-agonists in ARDS have failed and the reasons remain unclear. Cyclic nucleotide
phosphodiesterases (PDEs), the enzymes that degrade and inactivate cAMP, play a critical role in the
regulation of cellular cAMP levels, the subcellular compartmentalization of these signals, and hence endothelial
cell functions. Our preliminary data indicate that a single Type-4 PDE isoform, PDE4D, contributes the
predominant portion of cAMP-hydrolytic capacity in the pulmonary endothelium and is tightly regulated under
physiologic conditions. P.aeruginosa (PA) is a common cause of nosocomial pneumonia that can progress to
sepsis and ARDS. We observed that during the host-pathogen interaction, distinct PA virulence factors induce
PDE4D activation, resulting in a suppression and dysregulation of endothelial cAMP signals. Specifically, the
bacterial exotoxin cyclase ExoY promotes a PKA-mediated phosphorylation and activation of PDE4D that
alters endothelial cAMP signaling. In addition, PA infection can induce a PKA-independent, but type-3
secretion system- and flagellin-dependent PDE4D regulation that results in activation and subcellular
relocalization of the enzyme. With this proposal, we will define the pathways by which PA virulence factors
alter PDE4D functions and its contribution to endothelial barrier disruption and lung injury. We will test the idea
that PA-induced PDE4D activation correlates with health outcomes in patients with PA-associated ARDS, and
that, conversely, inhibition of PDE4 is endothelial barrier protective. We will test the idea that aberrant PDE4
activation limits the therapeutic efficacy of β-agonists in settings of PA-lung infection as well as other causes of
ARDS. The PDE4 family comprises four genes and non-selective PDE4 inhibitors have established therapeutic
effects in preclinical models of ARDS, but also induce side effects, such as emesis and nausea, that limit their
clinical utility. Given the unique and non-overlapping physiological and pathophysiological roles of each PDE4
isoform, targeting individual PDE4 proteins can serve to dissect the therapeutically beneficial from the side
effects of the PAN-PDE4 inhibitors available to date. To this end, we will determine whether selective ablation
of PDE4D is protective in ex vivo and in vivo models of PA-lung injury, paving the way for development of
PDE4D-selective inhibitors as ARDS therapeutics with an improved safety p...

## Key facts

- **NIH application ID:** 9901604
- **Project number:** 5R01HL141473-03
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** Wito H Richter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $378,245
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901604

## Citation

> US National Institutes of Health, RePORTER application 9901604, Regulation of phosphodiesterases and cAMP signaling during the host-pathogen interaction in the pulmonary endothelium (5R01HL141473-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901604. Licensed CC0.

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