Group II innate lymphoid cells and microvascular dysfunction from pulmonary titanium dioxide nanoparticle exposure

Background

The cardiovascular effects of pulmonary exposure to engineered nanomaterials (ENM) are poorly understood, and the reproductive consequences are even less understood. Inflammation remains the most frequently explored mechanism of ENM toxicity. However, the key mediators and steps between lung exposure and uterine health remain to be fully defined. The purpose of this study was to determine the uterine inflammatory and vascular effects of pulmonary exposure to titanium dioxide nanoparticles (nano-TiO₂). We hypothesized that pulmonary nano-TiO₂ exposure initiates a Th2 inflammatory response mediated by Group II innate lymphoid cells (ILC2), which may be associated with an impairment in uterine microvascular reactivity.

Methods

Female, virgin, Sprague-Dawley rats (8–12 weeks) were exposed to 100 μg of nano-TiO₂ via intratracheal instillation 24 h prior to microvascular assessments. Serial blood samples were obtained at 0, 1, 2 and 4 h post-exposure for multiplex cytokine analysis. ILC2 numbers in the lungs were determined. ILC2s were isolated and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) levels were measured. Pressure myography was used to assess vascular reactivity of isolated radial arterioles.

Results

Pulmonary nano-TiO₂ exposure was associated with an increase in IL-1ß, 4, 5 and 13 and TNF- α 4 h post-exposure, indicative of an innate Th2 inflammatory response. ILC2 numbers were significantly increased in lungs from exposed animals (1.66?±?0.19%) compared to controls (0.19?±?0.22%). Phosphorylation of the transactivation domain (Ser-468) of NF-κB in isolated ILC2 and IL-33 in lung epithelial cells were significantly increased (126.8?±?4.3% and 137?±?11% of controls respectively) by nano-TiO₂ exposure. Lastly, radial endothelium-dependent arteriolar reactivity was significantly impaired (27?±?12%), while endothelium-independent dilation (7?±?14%) and α-adrenergic sensitivity (8?±?2%) were not altered compared to control levels. Treatment with an anti- IL-33 antibody (1 mg/kg) 30 min prior to nano-TiO₂ exposure resulted in a significant improvement in endothelium-dependent dilation and a decreased level of IL-33 in both plasma and bronchoalveolar lavage fluid.

Conclusions

These results provide evidence that the uterine microvascular dysfunction that follows pulmonary ENM exposure may be initiated via activation of lung-resident ILC2 and subsequent systemic Th2-dependent inflammation.

     

Impaired Ciliogenesis in differentiating human bronchial epithelia exposed to non-Cytotoxic doses of multi-walled carbon Nanotubes

Background

Multi-walled carbon nanotubes (MWCNTs) are engineered nanomaterials used for a variety of industrial and consumer products. Their high tensile strength, hydrophobicity, and semi-conductive properties have enabled many novel applications, increasing the possibility of accidental nanotube inhalation by either consumers or factory workers. While MWCNT inhalation has been previously shown to cause inflammation and pulmonary fibrosis at high doses, the susceptibility of differentiating bronchial epithelia to MWCNT exposure remains unexplored. In this study, we investigate the effect of MWCNT exposure on cilia development in a differentiating air-liquid interface (ALI) model. Primary bronchial epithelial cells (BECs) were isolated from human donors via bronchoscopy and treated with non-cytotoxic doses of MWCNTs in submerged culture for 24 h. Cultures were then allowed to differentiate in ALI for 28 days in the absence of further MWCNT exposure. At 28 days, mucociliary differentiation endpoints were assessed, including whole-mount immunofluorescent staining, histological, immunohistochemical and ultrastructural analysis, gene expression, and cilia beating analysis.

Results

We found a reduction in the prevalence and beating of ciliated cells in MWCNT-treated cultures, which appeared to be caused by a disruption of cellular microtubules and cytoskeleton during ciliogenesis and basal body docking. Expression of gene markers of mucociliary differentiation, such as FOXJ1 and MUC5AC/B, were not affected by treatment. Colocalization of basal body marker CEP164 with γ-tubulin during days 1–3 of ciliogenesis, as well as abundance of basal bodies up to day 14, were attenuated by treatment with MWCNTs.

Conclusions

Our results suggest that a single exposure of bronchial cells to MWCNT during a vulnerable period before differentiation may impair their ability to develop into fully functional ciliated cells.

     

Nanoparticle inhalation augments particle-dependent systemic microvascular dysfunction

Background  

We have shown that pulmonary exposure to fine particulate matter (PM) impairs endothelium dependent dilation in systemic arterioles. Ultrafine PM has been suggested to be inherently more toxic by virtue of its increased surface area. The purpose of this study was to determine if ultrafine PM (or nanoparticle) inhalation produces greater microvascular dysfunction than fine PM. Rats were exposed to fine or ultrafine TiO₂ aerosols (primary particle diameters of ~1 μm and ~21 nm, respectively) at concentrations which do not alter bronchoalveolar lavage markers of pulmonary inflammation or lung damage.     

Usefulness of Intratracheal Instillation Studies for Estimating Nanoparticle-Induced Pulmonary Toxicity

Inhalation studies are the gold standard for the estimation of the harmful effects of respirable chemical substances, while there is limited evidence of the harmful effects of chemical substances by intratracheal instillation. We reviewed the effectiveness of intratracheal instillation studies for estimating the hazards of nanoparticles, mainly using papers in which both inhalation and intratracheal instillation studies were performed using the same nanoparticles. Compared to inhalation studies, there is a tendency in intratracheal instillation studies that pulmonary inflammation lasted longer in the lungs. A difference in pulmonary inflammation between high and low toxicity nanoparticles was observed in the intratracheal instillation studies, as in the inhalation studies. Among the endpoints of pulmonary toxicity, the kinetics of neutrophil counts, percentage of neutrophils, and chemokines for neutrophils and macrophages, heme oxygenase-1 (HO-1) in bronchoalveolar lavage fluid (BALF), reflected pulmonary inflammation, suggesting that these markers may be considered the predictive markers of pulmonary toxicity in both types of study. When comparing pulmonary inflammation between intratracheal instillation and inhalation studies under the same initial lung burden, there is a tendency that the inflammatory response following the intratracheal instillation of nanoparticles is greater than or equal to that following the inhalation of nanoparticles. If the difference in clearance in both studies is not large, the estimations of pulmonary toxicity are close. We suggest that intratracheal instillation studies can be useful for ranking the hazard of nanoparticles through pulmonary inflammation.     

Myeloid ABCG1 Deficiency Enhances Apoptosis and Initiates Efferocytosis in Bronchoalveolar Lavage Cells of Murine Multi-Walled Carbon Nanotube-Induced Granuloma Model

The use of carbon nanotubes has increased in the past few decades. Carbon nanotubes are implicated in the pathogenesis of pulmonary sarcoidosis, a chronic granulomatous inflammatory condition. We developed a murine model of chronic granulomatous inflammation using multiwall carbon nanotubes (MWCNT) to investigate mechanisms of granuloma formation. Using this model, we demonstrated that myeloid deficiency of ATP-binding cassette (ABC) cholesterol transporter (ABCG1) promotes granuloma formation and fibrosis with MWCNT instillation; however, the mechanism remains unclear. Our previous studies showed that MWCNT induced apoptosis in bronchoalveolar lavage (BAL) cells of wild-type (C57BL/6) mice. Given that continual apoptosis causes persistent severe lung inflammation, we hypothesized that ABCG1 deficiency would increase MWCNT-induced apoptosis thereby promoting granulomatous inflammation and fibrosis. To test our hypothesis, we utilized myeloid-specific ABCG1 knockout (ABCG1 KO) mice. Our results demonstrate that MWCNT instillation enhances pulmonary fibrosis in ABCG1 KO mice compared to wild-type controls. Enhanced fibrosis is indicated by increased trichrome staining and transforming growth factor-beta (TGF-β) expression in lungs, together with an increased expression of TGF-β related signaling molecules, interleukin-13 (IL-13) and Smad-3. MWCNT induced more apoptosis in BAL cells of ABCG1 KO mice. Initiation of apoptosis is most likely mediated by the extrinsic pathway since caspase 8 activity and Fas expression are significantly higher in MWCNT instilled ABCG1 KO mice compared to the wild type. In addition, TUNEL staining shows that ABCG1 KO mice instilled with MWCNT have a higher percentage of TUNEL positive BAL cells and more efferocytosis than the WT control. Furthermore, BAL cells of ABCG1 KO mice instilled with MWCNT exhibit an increase in efferocytosis markers, milk fat globule-EGF factor 8 (MFG-E8) and integrin β3. Therefore, our observations suggest that ABCG1 deficiency promotes pulmonary fibrosis by MWCNT, and this effect may be due to an increase in apoptosis and efferocytosis in BAL cells.     

Priming of Cardiopulmonary Bypass with Human Albumin Decreases Endothelial Dysfunction after Pulmonary Ischemia–Reperfusion in an Animal Model

The routine use of mechanical circulatory support during lung transplantation (LTx) is still controversial. The use of prophylactic human albumin (HA) or hypertonic sodium lactate (HSL) prime in mechanical circulatory support during LTx could prevent ischemia–reperfusion (IR) injuries and pulmonary endothelial dysfunction and thus prevent the development of pulmonary graft dysfunction. The objective was to investigate the impact of cardiopulmonary bypass (CPB) priming with HA and HSL compared to a CPB prime with Gelofusine (GF) on pulmonary endothelial dysfunction in a lung IR rat model. Rats were assigned to four groups: IR-CPB-GF group, IR-CPB-HA group, IR-CPB-HSL group and a sham group. The study of pulmonary vascular reactivity by wire myograph was the primary outcome. Glycocalyx degradation (syndecan-1 and heparan) was also assessed by ELISA and electron microscopy, systemic and pulmonary inflammation by ELISA (IL-1β, IL-10, and TNF-α) and immunohistochemistry. Clinical parameters were evaluated. We employed a CPB model with three different primings, permitting femoral–femoral assistance with left pulmonary hilum ischemia for IR. Pulmonary endothelium-dependent relaxation to acetylcholine was significantly decreased in the IR-CPB-GF group (11.9 ± 6.2%) compared to the IR-CPB-HA group (52.8 ± 5.2%, p < 0.0001), the IR-CPB-HSL group (57.7 ± 6.3%, p < 0.0001) and the sham group (80.8 ± 6.5%, p < 0.0001). We did not observe any difference between the groups concerning glycocalyx degradation, and systemic or tissular inflammation. The IR-CPB-HSL group needed more vascular filling and developed significantly more pulmonary edema than the IR-CPB-GF group and the IR-CPB-HA group. Using HA as a prime in CPB during Ltx could decrease pulmonary endothelial dysfunction’s IR-mediated effects. No effects of HA were found on inflammation.     

Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

Background  

The toxic and inflammatory potential of 5 different types of nanoparticles were studied in a sensitive model for pulmonary effects in apolipoprotein E knockout mice (ApoE^-/-). We studied the effects instillation or inhalation Printex 90 of carbon black (CB) and compared CB instillation in ApoE-/- and C57 mice. Three and 24 h after pulmonary exposure, inflammation was assessed by mRNA levels of cytokines in lung tissue, cell composition, genotoxicity, protein and lactate dehydrogenase activity in broncho-alveolar lavage (BAL) fluid.     

Ultrafine particles affect the balance of endogenous pro- and anti-inflammatory lipid mediators in the lung: in-vitro and in-vivo studies

ABSTRACT: BACKGROUND: Exposure to ultrafine particles exerts diverse harmful effects including aggravation ofpulmonary diseases like asthma. Recently we demonstrated in a mouse model for allergicairway inflammation that particle-derived oxidative stress plays a crucial role duringaugmentation of allergen-induced lung inflammation by ultrafine carbon particle (UfCP)inhalation. The mechanisms how particle inhalation might change the inflammatory balancein the lungs, leading to accelerated inflammatory reactions, remain unclear. Lipid mediators,known to be immediately generated in response to tissue injury, might be strong candidatesfor priming this particle-triggered change of the inflammatory balance. METHODS: We hypothesize that inhalation of UfCP may disturb the balance of pro- and antiinflammatorylipid mediators in: i) a model for acute allergic pulmonary inflammation,exposing mice for 24 h before allergen challenge to UfCP inhalation (51.7 nm, 507 ìg/m3),and ii) an in-vitro model with primary rat alveolar macrophages (AM) incubated with UfCP(10 ìg/1 x 106 cells/ml) for 1 h. Lungs and AM were analysed for pro- and anti-inflammatorylipid mediators, namely leukotriene B4 (LTB4), prostaglandin E2 (PGE2), 15(S)-hydroxyeicosatetraenoicacid (15(S)-HETE), lipoxin A4 (LXA4) and oxidative stress marker 8-isoprostane by enzyme immunoassays and immunohistochemistry. RESULTS: In non-sensitized mice UfCP exposure induced a light non-significant increase of all lipidmediators. Similarly but significantly in rat AM all lipid mediators were induced alreadywithin 1 h of UfCP stimulation. Also sensitized and challenge mice exposed to filtered airshowed a partially significant increase in all lipid mediators. In sensitized and challengedmice UfCP exposure induced highest significant levels of all lipid mediators in the lungstogether with the peak of allergic airway inflammation on day 7 after UfCP inhalation. Thelevels of LTB4, 8-isoprostane and PGE2 were significantly increased also one day after UfCPexposure. Immunohistochemistry localized highest concentrations of PGE2 especially in AMone day after UfCP exposure. CONCLUSION: Our results suggest that UfCP exposure affects the balance between pro- and antiinflammatorylipid mediators. In allergic mice, where the endogenous balance of pro- andanti-inflammatory mediators is already altered, UfCP exposure aggravates the inflammationand the increase in anti-inflammatory, pro-resolving lipid mediators is insufficient tocounterbalance the extensive inflammatory response. This may be a contributing mechanismthat explains the increased susceptibility of asthmatic patients towards particle exposure.     

Effect of particle dimension on biocompatibility of carbon nanomaterials

With various emerging applications ranging from medicine to materials and electronics, the risk of exposure to nanomaterials is rapidly increasing. Several routes of exposure to nanomaterials exist; the most important being dermal contact and inhalation. In this dermal toxicity study, the cellular effects of carbon-based materials with diameters ranging from micro- to nano-dimension were investigated using mouse keratinocytes (HEL-30). The carbon materials tested included carbon fibers (CF; 10 μm diameter), carbon nanofibers (CNF; 100 nm diameter), multi-walled carbon nanotubes (MWCNT; 10 nm diameter), and single-walled carbon nanotubes (SWCNT; 1 nm diameter). CF and CNF did not significantly affect cell viability; however, MWCNT and SWCNT reduced cell viability in a time-dependent manner up to 48 h, with full recovery of mitochondrial function by the 72 h time point. After a 24 h exposure, cells exposed to MWCNT produced up to 3-fold higher increase in reactive oxygen species than those exposed to SWCNT. The results of this study suggest that high-aspect ratio carbon material toxicity is dependent on dimension and composition.     

Usefulness of myeloperoxidase as a biomarker for the ranking of pulmonary toxicity of nanomaterials

Background

In order to examine whether myeloperoxidase (MPO) can be a useful marker for evaluating the pulmonary toxicity of nanomaterials, we analyzed MPO protein in bronchoalveolar lavage fluid (BALF) samples obtained from previous examinations of a rat model. In those examinations we performed intratracheal instillation exposures (dose: 0.2–1.0 mg) and inhalation exposures (exposure concentration: 0.32–10.4 mg/m³) using 9 and 4 nanomaterials with different toxicities, respectively. Based on those previous studies, we set Nickel oxide nanoparticles (NiO), cerium dioxide nanoparticles (CeO₂), multi wall carbon nanotubes with short or long length (MWCNT (S) and MWCNT (L)), and single wall carbon nanotube (SWCNT) as chemicals with high toxicity; and titanium dioxide nanoparticles (TiO₂ (P90) and TiO₂ (Rutile)), zinc oxide nanoparticles (ZnO), and toner with external additives including nanoparticles as chemicals with low toxicity. We measured the concentration of MPO in BALF samples from rats from 3 days to 6 months following a single intratracheal instillation, and from 3 days to 3 months after the end of inhalation exposure.

Results

Intratracheal instillation of high toxicity NiO, CeO_2, MWCNT (S), MWCNT (L), and SWCNT persistently increased the concentration of MPO, and inhalation of NiO and CeO₂ increased the MPO in BALF. By contrast, intratracheal instillation of low toxicity TiO₂ (P90), TiO₂ (Rutile), ZnO, and toner increased the concentration of MPO in BALF only transiently, and inhalation of TiO₂ (Rutile) and ZnO induced almost no increase of the MPO. The concentration of MPO correlated with the number of total cells and neutrophils, the concentration of chemokines for neutrophils (cytokine-induced neutrophil chemoattractant (CINC)-1 and heme oxygenase (HO)-1), and the activity of released lactate dehydrogenase (LDH) in BALF. The results from the receiver operating characteristics (ROC) for the toxicity of chemicals by the concentration of MPO proteins in the intratracheal instillation and inhalation exposures showed that the largest areas under the curves (AUC) s in both examinations occurred at 1 month after exposure.

Conclusion

These data suggest that MPO can be a useful biomarker for the ranking of the pulmonary toxicity of nanomaterials, especially at 1 month after exposure, in both intratracheal instillation and inhalation exposure.

     

Combustion-derived nanoparticles: A review of their toxicology following inhalation exposure

This review considers the molecular toxicology of combustion-derived nanoparticles (CDNP) following inhalation exposure. CDNP originate from a number of sources and in this review we consider diesel soot, welding fume, carbon black and coal fly ash. A substantial literature demonstrates that these pose a hazard to the lungs through their potential to cause oxidative stress, inflammation and cancer; they also have the potential to redistribute to other organs following pulmonary deposition. These different CDNP show considerable heterogeneity in composition and solubility, meaning that oxidative stress may originate from different components depending on the particle under consideration. Key CDNP-associated properties of large surface area and the presence of metals and organics all have the potential to produce oxidative stress. CDNP may also exert genotoxic effects, depending on their composition. CDNP and their components also have the potential to translocate to the brain and also the blood, and thereby reach other targets such as the cardiovascular system, spleen and liver. CDNP therefore can be seen as a group of particulate toxins unified by a common mechanism of injury and properties of translocation which have the potential to mediate a range of adverse effects in the lungs and other organs and warrant further research.     

Molecular Framework of Mouse Endothelial Cell Dysfunction during Inflammation: A Proteomics Approach

A key aspect of cytokine-induced changes as observed in sepsis is the dysregulated activation of endothelial cells (ECs), initiating a cascade of inflammatory signaling leading to leukocyte adhesion/migration and organ damage. The therapeutic targeting of ECs has been hampered by concerns regarding organ-specific EC heterogeneity and their response to inflammation. Using in vitro and in silico analysis, we present a comprehensive analysis of the proteomic changes in mouse lung, liver and kidney ECs following exposure to a clinically relevant cocktail of proinflammatory cytokines. Mouse lung, liver and kidney ECs were incubated with TNF-α/IL-1β/IFN-γ for 4 or 24 h to model the cytokine-induced changes. Quantitative label-free global proteomics and bioinformatic analysis performed on the ECs provide a molecular framework for the EC response to inflammatory stimuli over time and organ-specific differences. Gene Ontology and PANTHER analysis suggest why some organs are more susceptible to inflammation early on, and show that, as inflammation progresses, some protein expression patterns become more uniform while additional organ-specific proteins are expressed. These findings provide an in-depth understanding of the molecular changes involved in the EC response to inflammation and can support the development of drugs targeting ECs within different organs. Data are available via ProteomeXchange (identifier PXD031804).     

Exposure to ultrafine carbon particles at levels below detectable pulmonary inflammation affects cardiovascular performance in spontaneously hypertensive rats

Background

Exposure to particulate matter is a risk factor for cardiopulmonary disease but the underlying molecular mechanisms remain poorly understood. In the present study we sought to investigate the cardiopulmonary responses on spontaneously hypertensive rats (SHRs) following inhalation of UfCPs (24 h, 172 μg·m^-3), to assess whether compromised animals (SHR) exhibit a different response pattern compared to the previously studied healthy rats (WKY).

Methods

Cardiophysiological response in SHRs was analyzed using radiotelemetry. Blood pressure (BP) and its biomarkers plasma renin-angiotensin system were also assessed. Lung and cardiac mRNA expressions for markers of oxidative stress (hemeoxygenase-1), blood coagulation (tissue factor, plasminogen activator inhibitor-1), and endothelial function (endothelin-1, and endothelin receptors A and B) were analyzed following UfCPs exposure in SHRs. UfCPs-mediated inflammatory responses were assessed from broncho-alveolar-lavage fluid (BALF).

Results

Increased BP and heart rate (HR) by about 5% with a lag of 1–3 days were detected in UfCPs exposed SHRs. Inflammatory markers of BALF, lung (pulmonary) and blood (systemic) were not affected. However, mRNA expression of hemeoxygenase-1, endothelin-1, endothelin receptors A and B, tissue factor, and plasminogen activator inhibitor showed a significant induction (~2.5-fold; p < 0.05) with endothelin 1 being the maximally induced factor (6-fold; p < 0.05) on the third recovery day in the lungs of UfCPs exposed SHRs; while all of these factors – except hemeoxygenase-1 – were not affected in cardiac tissues. Strikingly, the UfCPs-mediated altered BP is paralleled by the induction of renin-angiotensin system in plasma.

Conclusion

Our finding shows that UfCPs exposure at levels which does not induce detectable pulmonary neutrophilic inflammation, triggers distinct effects in the lung and also at the systemic level in compromised SHRs. These effects are characterized by increased activity of plasma renin-angiotensin system and circulating white blood cells together with moderate increases in the BP, HR and decreases in heart rate variability. This systemic effect is associated with pulmonary, but not cardiac, mRNA induction of biomarkers reflective of oxidative stress; activation of vasoconstriction, stimulation of blood coagulation factors, and inhibition of fibrinolysis. Thus, UfCPs may cause cardiovascular and pulmonary impairment, in the absence of detectable pulmonary inflammation, in individuals suffering from preexisting cardiovascular diseases.     

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague–Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25–34 kDa, and 34–50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.     

The Potential Role of Kallistatin in the Development of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a vascular condition that causes permanent dilation of the abdominal aorta, which can lead to death due to aortic rupture. The only treatment for AAA is surgical repair, and there is no current drug treatment for AAA. Aortic inflammation, vascular smooth muscle cell apoptosis, angiogenesis, oxidative stress and vascular remodeling are implicated in AAA pathogenesis. Kallistatin is a serine proteinase inhibitor, which has been shown to have a variety of functions, potentially relevant in AAA pathogenesis. Kallistatin has been reported to have inhibitory effects on tumor necrosis factor alpha (TNF-α) signaling induced oxidative stress and apoptosis. Kallistatin also inhibits vascular endothelial growth factor (VEGF) and Wnt canonical signaling, which promote inflammation, angiogenesis, and vascular remodeling in various pre-clinical experimental models. This review explores the potential protective role of kallistatin in AAA pathogenesis.     

Coating carbon nanotubes with a polystyrene-based polymer protects against pulmonary toxicity

Background

Multi-walled carbon nanotubes (MWCNTs) are widely used in many disciplines due to their unique physical and chemical properties. Therefore, some concerns about the possible human health and environmental impacts of manufactured MWCNTs are rising. We hypothesized that instillation of MWCNTs impairs pulmonary function in C57BL/6 mice due to development of lung inflammation and fibrosis.

Methods

MWCNTs were administered to C57BL/6 mice by oropharyngeal aspiration (1, 2, and 4 mg/kg) and we assessed lung inflammation and fibrosis by inflammatory cell infiltration, collagen content, and histological assessment. Pulmonary function was assessed using a FlexiVent system and levels of Ccl3, Ccl11, Mmp13 and IL-33 were measured by RT-PCR and ELISA.

Results

Mice administered MWCNTs exhibited increased inflammatory cell infiltration, collagen deposition and granuloma formation in lung tissue, which correlated with impaired pulmonary function as assessed by increased resistance, tissue damping, and decreased lung compliance. Pulmonary exposure to MWCNTs induced an inflammatory signature marked by cytokine (IL-33), chemokine (Ccl3 and Ccl11), and protease production (Mmp13) that promoted the inflammatory and fibrotic changes observed within the lung.

Conclusions

These results further highlight the potential adverse health effects that may occur following MWCNT exposure and therefore we suggest these materials may pose a significant risk leading to impaired lung function following environmental and occupational exposures.