# Mechanisms underlying metal nanoparticle-induced lung injury and fibrosis

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2022 · $391,145

## Abstract

Metal nanoparticles have been widely used in cosmetics, medicine, electronics, and industry, and occupational
or non-occupational exposure to metal nanoparticles is growing. In this proposal, we have selected several
transition metal nanoparticles (Nano-Co, Nano-Ni, and Nano-TiO2) as `model' metal nanoparticles to examine
their ability to induce pulmonary injury and fibrosis and the potential underlying mechanisms involved. An
inflammasome is a multiprotein complex that serves as a platform for caspase-1-dependent proteolytic
maturation and secretion of interleukin-1β (IL-1β). The central component of an inflammasome is a member of
the NLRP family, and this protein associates with the adaptor protein ASC, which in turn recruits pro-inflammatory
caspase precursors (such as procaspase-1). Among a number of inflammasomes, the NLRP3 inflammasome is
the most extensively studied. Our working hypothesis is that exposure to metal nanoparticles will cause
activation and/or dysregulation of the inflammasome and IL-1β secretion in alveolar macrophages (AMs),
lung epithelial cells, and lung fibroblasts, which will cause dysregulation of matrix metalloproteinases
(MMPs) and tissue inhibitors of metalloproteinases (TIMPs), initiating and promoting metal nanoparticle-
induced pulmonary injury and fibrosis. This project will use both in vitro and in vivo systems to address the
following specific aims: (1) Determine the role of inflammasome activation in IL-1β secretion induced by
metal nanoparticles in vitro and in vivo. We will identify whether activation of the inflammasome is involved
in metal nanoparticle-induced IL-1β secretion in alveolar macrophages (AMs), lung epithelial cells, and lung
fibroblasts by: (1) using ac-YVAD-cmk, a particular inhibitor of caspase-1; (2) knocking-down one of the
inflammasome components such as NLRP3, ASC, or caspase-1 by using CRISPR/Cas9 technology; and (3)
using NLRP3 or ASC knock-out mice. We will then determine whether NADPH oxidase- and/or mitochondria-
dependent ROS generation and potassium efflux are involved in metal nanoparticle-induced inflammasome
activation and IL-1β secretion. We will also measure IL-1β secretion in mice exposed to metal nanoparticles. (2)
Examine the role of IL-1β in the alteration of MMPs and TIMPs expression and activity in lung cells
exposed to metal nanoparticles. While IL-1β is an inducer for MMP-2 and MMP-9 activity, it is unclear how it
regulates MMPs and TIMPs with exposure to metal nanoparticles. To test the role of the inflammasome and IL-
1β in the regulation of MMPs and TIMPs, the strategies in Aim 1 will be used to inhibit inflammasome function,
and strategies to inhibit IL-1 function will be applied by using: (1) the pharmacologic IL-1β inhibitor; (2) anti-IL-
1β antibody; and (3) IL-1RI-/- mice that will not respond to IL-1β. After exposure to metal nanoparticles, MMP-2,
MMP-9 and TIMPs expression and activity will be determined. (3) Investigate the role of inflammasome
activation ...

## Key facts

- **NIH application ID:** 10401441
- **Project number:** 5R01HL147856-04
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Qunwei Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,145
- **Award type:** 5
- **Project period:** 2019-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401441

## Citation

> US National Institutes of Health, RePORTER application 10401441, Mechanisms underlying metal nanoparticle-induced lung injury and fibrosis (5R01HL147856-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401441. Licensed CC0.

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