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

BACKGROUND: Nanoparticles 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. METHODS: Acute 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. RESULTS: Some 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. CONCLUSIONS: Our data provide molecular insight into PAMAM nanoparticle-induced lung injury and suggest potential therapeutic and screening strategies to address the safety of nanomaterials.

Avian influenza viruses suppress innate immunity by inducing trans-transcriptional readthrough via SSU72.

Innate immunity plays critical antiviral roles. The highly virulent avian influenza viruses (AIVs) H5N1, H7N9, and H5N6 can better escape host innate immune responses than the less virulent seasonal H1N1 virus. Here, we report a mechanism by which transcriptional readthrough (TRT)-mediated suppression of innate immunity occurs post AIV infection. By using cell lines, mouse lungs, and patient PBMCs, we showed that genes on the complementary strand ("trans" genes) influenced by TRT were involved in the disruption of host antiviral responses during AIV infection. The trans-TRT enhanced viral lethality, and TRT abolishment increased cell viability and STAT1/2 expression. The viral NS1 protein directly bound to SSU72, and degradation of SSU72 induced TRT. SSU72 overexpression reduced TRT and alleviated mouse lung injury. Our results suggest that AIVs infection induce TRT by reducing SSU72 expression, thereby impairing host immune responses, a molecular mechanism acting through the NS1-SSU72-trans-TRT-STAT1/2 axis. Thus, restoration of SSU72 expression might be a potential strategy for preventing AIV pandemics.

FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice.

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme 2 (ACE2), which in turn converts angiotensin II to angiotensin-(1-7), then inhibits hypertension and reverses vascular damage. In addition, ACE2 deficiency strikingly abrogates these beneficial effects of FGF21 in mice, including alleviation of angiotensin II-associated hypertension and vascular damage. Otherwise, pharmaceutical inhibition of angiotensin-(1-7) attenuates the protective effect of FGF21 on angiotensin II-induced vascular dysfunction, but not on hypertension. Thus, FGF21 protects against angiotensin II-induced hypertension and vascular impairment by activation of the ACE2/angiotensin-(1-7) axis via fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels.

Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections.

The potential for avian influenza H5N1 outbreaks has increased in recent years. Thus, it is paramount to develop novel strategies to alleviate death rates. Here we show that avian influenza A H5N1-infected patients exhibit markedly increased serum levels of angiotensin II. High serum levels of angiotensin II appear to be linked to the severity and lethality of infection, at least in some patients. In experimental mouse models, infection with highly pathogenic avian influenza A H5N1 virus results in downregulation of angiotensin-converting enzyme 2 (ACE2) expression in the lung and increased serum angiotensin II levels. Genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice, confirming a role of ACE2 in H5N1-induced lung pathologies. Administration of recombinant human ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice. Our data link H5N1 virus-induced acute lung failure to ACE2 and provide a potential treatment strategy to address future flu pandemics.

Functionalized single-walled carbon nanotubes cause reversible acute lung injury and induce fibrosis in mice.

Nanotechnology is one of today's most promising technological developments, but safety concerns raise questions about its development. Risk assessments of nanomaterials during occupational exposure are crucial for their development. Here, we assessed the lung toxicity of functionalized single-walled carbon nanotube (f-SWCNT) exposure in C57BL/6 mice, elucidated the underlying molecular mechanism, and evaluated the self-repair ability and lung fibrosis of the mice. Soluble f-SWCNTs were administered to mice. After 18 h or 14 days, the lung histopathology, bronchoalveolar lavage fluid, lung edema, vascular permeability, and PaO(2) levels were evaluated, and biochemical and immunostaining tests were also performed. We found that some f-SWCNTs could induce acute lung injury (ALI) in mice via proinflammatory cytokine storm signaling through the NF-κB pathway in vivo. We illustrated that corticosteroid treatments could ameliorate the ALI induced by the f-SWCNTs in mice. Surprisingly, the ALI was almost completely reversed within 14 days, while mild to moderate fibrosis, granuloma, and DNA damage remained in the mice at day 14. Our studies indicate potential remedies to address the growing concerns about the safety of nanomaterials. In addition, we notify that the type of functional groups should be considered in nanomedicine application as differently functionalized SWCNTs generated different effects on the lung toxicity.