Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation

Particle and Fibre Toxicology

Katherine Zychowski¹  Ekaterina Mostovenko²  Andrew K. Ottens²  Ting Wang³  Guy Herbert⁴  Jesse L. Denson⁴  Russell Hunter⁴  Selita N. Lucas⁴  Matthew J. Campen⁴  Jessica G. Begay⁴  Tamara L. Young⁴  Raul Salazar⁴  Aaron Erdely⁵  Kelly Fraser⁵ 

[1] College of Nursing, University of New Mexico, 87131, Albuquerque, NM, USA;Department of Anatomy and Neurobiology, Virginia Commonwealth University, PO Box 980709, 23298, Richmond, VA, USA;Department of Internal Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA;Department of Pharmaceutical Sciences, MSC09 5360, 1 University of New Mexico, 87131-0001, Albuquerque, NM, USA;Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 26505, Morgantown, WV, USA;

关键词: Multiwall carbon nanotube (MWCNT);    Carbon nanotubes;    Nanoparticles;    Nanomaterials;    Matrix metalloproteinase;    Inflammation;    Serum-bioactivity;    Biomarker;   

DOI  :  10.1186/s12989-021-00427-w

来源: Springer

【 摘 要 】

BackgroundMultiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity.ResultsC57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNF-α), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice.ConclusionsThus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.

【 授权许可】

CC BY