# Regulation of portal hypertension through neutrophil-platelet interactions in liver sinusoids

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2022 · $167,940

## Abstract

PROJECT ABSTRACT
Portal hypertension (PHTN) is a common final pathway of multiple forms of chronic liver disease which
accounts for significant morbidity and mortality among patients with liver disease. However, there is a paucity
of therapies available to ameliorate PHTN. The overall objective of this proposal is to elucidate the
contribution of neutrophils and platelets to the pathogenesis of PHTN, with the therapeutic goal of facilitating
the design of therapies to decrease portal pressure. The pathophysiology of PHTN is complex and is regulated
at multiple levels, including paracrine signaling within sinusoids, formation of microvascular thrombosis, and
endothelial dysfunction. We have previously identified a novel but critical role of neutrophils in the
pathogenesis of PHTN. We found that cyclic stretch imposed by congestive hepatopathy (CH) induces
activation of mechanosensitive Piezo channels within liver sinusoidal endothelial cells (LSECs). Piezo
channels activate mechanocrine signaling pathways which culminate in secretion of the neutrophil chemotactic
cytokine CXCL1. CXCL1 induces infiltration of neutrophils into liver sinusoids. Neutrophils form complexes with
platelets which lead to the formation of neutrophil extracellular traps, or NETs. We found that genetic and
pharmacologic inhibition of NET formation significantly decreases portal pressures in murine models of CH and
PHTN. Although platelets have been implicated in NET formation in certain settings, the mechanisms which
recruit platelets and regulate their interactions with neutrophils to generate sinusoidal NETs require further
investigation. Weibel-Palade bodies (WPBs) are endothelial organelles which generate extracellular vesicles
(EVs) containing inflammatory and hemostatic factors. The impact of WPB-derived EVs on platelet recruitment
to liver sinusoids has not been studied. We have formulated the central hypothesis that platelets activated by
WPB-derived EVs interact with the CD11b/CD18 integrin receptor on neutrophils to stimulate NET formation
and PHTN. We will test this hypothesis through the following independent but integrated specific aims which
are both technically and conceptually innovative. First, we will test the hypothesis that Piezo channels
serve as master mechanosensors whose activation regulates the generation of both neutrophil- and platelet-
chemotactic factors which modulate portal pressures. We propose that Piezo activation generates platelet
chemotactic factors within EVs derived from WPBs in LSECs. Finally, using murine models and clinically-
relevant forms of platelet inhibition, we will test the hypothesis that interaction of the neutrophil integrin receptor
CD11b/CD18 with the platelet glycoprotein receptor GPIbα drives NET formation. Our proposal is significant
because it has the potential to elucidate novel therapeutic targets to better manage PHTN, a devastating and
prevalent disease which is currently curable only with liver transplantation.

## Key facts

- **NIH application ID:** 10541034
- **Project number:** 7K08DK127064-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Moira B Hilscher
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $167,940
- **Award type:** 7
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10541034

## Citation

> US National Institutes of Health, RePORTER application 10541034, Regulation of portal hypertension through neutrophil-platelet interactions in liver sinusoids (7K08DK127064-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10541034. Licensed CC0.

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