Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice

Abstract

BackgroundNanoparticles have become a key technology in multiple industries. However, there are growing reports of the toxicity of nanomaterials to humans. In particular, nanomaterials have been linked to lung diseases. The molecular mechanisms of nanoparticle toxicity are largely unexplored.MethodsAcute lung injury was induced in wild-type mice and angiotensin-coverting enzyme 2 (ACE2) knockout mice by the intratracheal instillation of cationic polyamidoamine dendrimer (PAMAM) nanoparticles. For rescue experiments, losartan (15 mg/kg in PBS) was injected intraperitoneally 30 min before nanoparticle administration.ResultsSome PAMAM nanoparticles, but not anionic PAMAM nanoparticles or carbon nanotubes, triggered acute lung failure in mice. Mechanistically, cationic nanoparticles can directly bind ACE2, decrease its activity and down-regulate its expression level in lung tissue, resulting in deregulation of the renin-angiotensin system. Gene inactivation of Ace2 can exacerbate lung injury. Importantly, the administration of losartan, which is an angiotensin II type I receptor antagonist, can ameliorate PAMAM nanoparticle-induced lung injury.ConclusionsOur data provide molecular insight into PAMAM nanoparticle-induced lung injury and suggest potential therapeutic and screening strategies to address the safety of nanomaterials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-015-0080-x) contains supplementary material, which is available to authorized users.

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“…We demonstrated that the ARB losartan could attenuate acute lung failure in a mouse model whose condition had been worsened after injection of the SARS-CoV-2 spike protein 9 . We also showed imbalanced RAAS in many predisposing conditions for ARDS, including sepsis, acid aspiration, bacteria, SARS-CoV-2, avian influenza (H5N1 and H7N9) infections, as well as nanoparticle aspiration 9 , 11 – 13 , 23 . These studies suggested that blocking the RAAS pathway and reducing angiotensin II levels could ameliorate lung injury 9 , 11 , 12 , 16 , 23 .…”

“…Although a wide variety of conditions, including SARS-CoV, sepsis, acid aspiration, bacteremia, and avian influenza (H5N1 and H7N9) infections, predispose patients to ARDS, a common mechanism seems to be an imbalance of RAAS 9 , 11 – 13 , 23 . Our previous studies in mice suggested that ACE, angiotensin II, and the type 1a angiotensin II receptor participate in disease pathogenesis, whereas ACE2 and the type 2a angiotensin II receptor could protect the mice from severe acute lung injury 9 , 12 .…”

Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo

“…The data presented here also lend further support to the assertion that drug delivery systems cannot be considered as biologically inert and aside from their ability to improve drug delivery have additional, sometimes unexpected, biological and cellular effects [ 15 – 17 , 65 ]. Our study shows that in vivo modulation of the highly important EGFR cell signal transduction pathway can also be added to the growing list of intrinsic biological activities for PAMAM dendrimers that includes eliciting multiple gene expression changes in biological systems that may impact on siRNA activity and specificity [ 18 , 66 ], disrupting key platelet function [ 67 ], modulating Angiotensin-converting enzyme 2 activity [ 68 ] and exhibiting anti-inflammatory activity [ 20 , 38 ].…”

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“…For example, phagocyte cells internalize spherical-shaped nanoparticles more easily than stretched-shaped structures ( 228 ). And although positively charged particles are taken up more avidly, negatively charged particles have been shown to exhibit lower toxicity ( 229 – 232 ). Nanoparticles can be made from different materials, metallic (e.g., silver, gold, and copper), magnetic (e.g., iron) (useful for imaging), ceramic, carbon-based, silica, lipid-based, or polymeric such as poly(amino acids), polysaccharides and poly(alpha-hydroxy acids).…”