Impact of Particles on Pulmonary Endothelial Cells

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1		Marina Almeida-Silva	--	3212	2022-06-14 11:46:13	\|
2	layout	Camila Xu	Meta information modification	3212	2022-06-15 02:32:22	\|

This entry is adapted from the peer-reviewed paper 10.3390/toxics10060312

Due to particle sizes ranging from the nanometre to the millimetre scale, these particles can be easily inhaled or absorbed by the skin, reaching the cells of the pulmonary alveoli and finally entering the bloodstream, which can lead to health adverse effects. Endothelial cells (ECs) guarantee permeability for the passage of blood, hormone fluids, macromolecules and platelets through arteries, veins, arterioles and venules and controls blood flow and vascular relaxation and constriction. The function of pulmonary endothelial cells (PECs) is not very different from vascular endothelial cells; they regulate blood flow but also control the passage of liquid and macromolecules between the interstitial space, the vessels and the smooth muscle cells.

pulmonary endothelial cells particles impact exposure

1. Introduction

Air quality has a significant influence in human health and well-being ^[1], and it has been recognised that air pollution contributes to severe respiratory diseases such as asthma and chronic obstructive pulmonary disorder (COPD) ^[2]. An aerosol is an aggregation of solid or liquid particles dispersed in the air, which can be found in the form of dust or fumes. Due to particle sizes ranging from the nanometre to the millimetre scale, these particles can be easily inhaled or absorbed by the skin, reaching the cells of the pulmonary alveoli and finally entering the bloodstream, which can lead to health adverse effects ^[3]^[4]. These include proinflammatory responses in vivo, such as the increased production of reactive oxygen species (ROS), the altered transcription of genes related to inflammation, the polarisation of macrophages and the overproduction of proinflammatory molecules ^[5]. Ultimately, be exposed to aerosol induces cardiovascular and respiratory diseases that, in some cases, might be fatal ^[1].

Air pollutants such as particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), carbon monoxide (CO), gaseous mixtures of nitrogen dioxide and volatile organic compounds can lead to severe lung damage and respiratory diseases such as asthma, bronchitis and chronic obstructive pulmonary disorder ^[2]. It is now known that the guidelines for air quality are not met in the 115 largest cities in the European Union (EU), which affects around 40 million people, ultimately leading to 21,000 premature deaths per year ^[6]. In Southeast Asia, it was estimated that in 2016, air pollution resulted in about 2.4 million premature deaths ^[6]. In other regions, in 2012, the number of deaths was also high: 194,000 deaths in the Eastern Mediterranean, 1.1 million in the Western Pacific and 211,000 deaths in Sub-Saharan Africa ^[7]. Accordingly, the research of the molecular mechanisms behind the effects of air pollutants on human health is mandatory. Among the most common and studied air pollutants are PM, cigarette smoke (CS), diesel exhaust particles (DEPs) and carbon black (CB).

Exposure to PM, specifically the particles derived from combustion, has increased significantly in Western countries in the last 250 years due to globalisation developments and industrialisation, such as increased traffic and shipping activities. This has led to the presence of substantial quantities of coarse (aerodynamic diameter < 10 μm—PM10), fine (aerodynamic diameter < 2.5 μm—PM2.5) and ultrafine (aerodynamic diameter < 0.1 μm—PM0.1) particles in the near-surface atmosphere ^[8]. Epidemiological and experimental studies have proven that exposure to atmospheric PM, especially fine particulate matter with sizes of 2.5 µm (PM2.5) or below, contributes to 3.3 million premature deaths per year worldwide ^[9], which are caused by respiratory and cardiovascular diseases such as ischemic heart disease, COPD, acute lower respiratory illness and lung cancer ^[5]. Studies have also shown that PM accelerates inflammation-mediated thrombosis ^[9]. It has been estimated that exposure to high concentrations of PM2.5 affects approximately 92% of the world’s population in areas with adverse air quality ^[1].

Nearly 1.25 billion people smoke cigarettes daily worldwide ^[10]. CS is a highly complex mixture that contains more than 4000 compounds, such as nicotine, a component of the tar phase that is the addictive substance of cigarette smoke ^[11]. Environmental tobacco smoke is generated from the combination of sidestream smoke (85%), smoke emanated from the burning part of a cigarette which contains a higher concentration of toxic gaseous constituents, and a small fraction of exhaled mainstream smoke (15%), which is smoke that is drawn through the tobacco into an active smoker’s mouth, which contains 8% tar and 92% gaseous components ^[11]. CS is linked to the most common causes of death in the elderly and contributes to the morbidity and disability rates associated with many chronic illnesses that are common in this age group ^[12].

Ambient air pollution by DEPs is a major cause of cardiovascular and metabolic mortality worldwide ^[13]. Diesel is a complex mixture of solid and liquid material with respirable size that can penetrate deep into human lungs ^[14]. DEPs combine approximately 20% ambient PM and belong to the fine (PM2.5) and ultrafine particle fractions (PM0.1); exposure to DEPs can impair endothelial and fibrinolytic functions, promote blood thrombogenicity and increase the gravity of cardiac ischemia in humans ^[13].

CB is a fine material that is used as a black pigment and is produced by the thermal decomposition of liquid or gaseous hydrocarbons under controlled conditions, which mainly consist of elemental carbon, with the rest being hydrogen, sulphur, oxygen, organic carbon, extractable organic materials and ash ^[15]. CB has high chemical stability and electrical conductivity and is a conductive additive ^[16]. Exposure to CB occurs in workers in industries that produce rubber and fortify vehicle tires and other rubber products, and it is used in coatings, plastics, inks or paints, ceramics, paper, battery production, carbon electrode production and in metallurgical processes such as carburisation ^[15]. In terms of the effects of CB on cells, it has been demonstrated that it strongly induces the production of reactive oxygen species (ROS) ^[17]. Additionally, studies on mice regarding gestation with CB through intratracheal instillation showed a change in testicular structure and reduced daily sperm production ^[18].

It has long been suggested in studies, in vitro and in vivo, that PM, CS, DEPs and CB can affect the endothelium and its cells, inducing lung injury and inflammation via endothelial dysfunction ^[13]^[19]^[20]^[21].

The endothelium is a layer that covers the interior of the walls of arteries, capillaries, veins and the lymphatic system ^[19]. This monolayer plays an active role by regulating the environment, responding to external stresses and also presenting itself as an endocrine and metabolic tissue ^[22]. Endothelial cells (ECs) guarantee permeability for the passage of blood, hormone fluids, macromolecules and platelets through arteries, veins, arterioles and venules and controls blood flow and vascular relaxation and constriction ^[23]^[24]^[25]. ECs secrete mediators and signalling molecules that regulate blood clotting to prevent platelet adhesion and aggregation in conditions of homeostasis ^[19]. The structure, characterisation and function of ECs vary according to their location ^[19]. Their structural heterogeneity includes differences in size, thickness, the position of the nuclei ^[19], changes in the genetic expression and in the production of the extracellular matrix and in the properties of the cell surface ^[25]. The function of pulmonary endothelial cells (PECs) is not very different from vascular endothelial cells; they regulate blood flow but also control the passage of liquid and macromolecules between the interstitial space, the vessels and the smooth muscle cells ^[26]^[27]^[28]. The role of PECs in haemostasis regulation can have opposite effects, as it displays anticoagulant, antiplatelet and fibrinolytic properties, whereas it promotes contrasting responses in the case of injury ^[29]. It also regulates the synthesis and metabolism of vasoactive compounds, which are regulators of pulmonary lung tone, such as endothelin-1 (ET-1) and nitrogen monoxide (NO) ^[30].

2. Impact of Particles on Pulmonary Endothelial Cells

2.1. Particulate Matter

Particulate matter (PM) can cause respiratory and cardiovascular diseases such as chronic obstructive pulmonary disease, ischemic heart disease, COPD, acute lower respiratory illness and lung cancer ^[5]. It affects around 40 million people, ultimately leading to 21,000 premature deaths per year ^[6]. Exposure to PM comes from combustion and can be presented in different sizes.

The results show that PM induces the disruption of the lung endothelial barrier through the induction of ROS and concomitant oxidative stress ^[31]^[32], with the activation of the p38 MAPK and HSP27 signalling pathways ^[32]. In particular, it was observed that the PM-induced phosphorylation of HSP27, an important protein in regulating actin polymerisation ^[33], leads to a contractile cytoskeletal arrangement ^[32] and that actin filament reorganisation was dependent on ROS production and p38 MAPK activation ^[32]. Accordingly, in order to protect endothelial integrity against PM exposure, it is necessary to restrain the activation of the p38–HSP27 pathway through the inhibition of oxidative stress ^[32]. Similarly, Karki, P. et al. ^[34] revealed that the effects of PM on EC barrier dysfunction were dependent on the production of ROS, which induced the production of truncated oxidised phospholipids (Tr-OxPLs). These events resulted in the destabilisation of cell junctions, as Tr-OxPLs induce the phosphorylation of the adherent junction VE-cadherin, which results in its internalisation with concomitant rescue from the plasma membrane ^[34]. Accordingly, the uncontrolled production of ROS seems to play a critical role in the PM-mediated effects on ECs. This event is caused by different mechanisms such as the activation of pro-oxidant enzymes and mitochondrial damages, and it constitutes a recognised mechanism of inflammation and cellular damage ^[34].

Endothelial cells are the main tight-junction-associated cellular barriers for pulmonary gas exchange, and normally, they are impermeable to albumin and leukocytes. The place of adhesion between leukocytes and endothelial cells is determined by the presence of molecules such as VCAM-1, a very important marker for leukocytes, including PMNs ^[35]. The data collected showed that PMNs treated with PM2.5 are able to bind sVCAM-1 and that PM2.5 exposure induces PMN infiltration with increased VCAM-1 ^[35]. Furthermore, it was demonstrated that short-term exposure to PM2.5 increases neutrophil count in the peripheral blood and the neutrophil to WBC ratio, which indicated that PMNs participate in PM2.5-induced inflammatory-lung injury. This hypothesis was confirmed when PM2.5-induced lung injury was reversed by the depletion of circulatory PMNs before PM2.5 exposure ^[35]. Furthermore, as PM2.5 deposits in the alveolar space and ECs, it causes lung oedema, morphological changes and cell barrier disruption ^[35]. When it comes to ultrafine PM, mainly PM1, the decrease in cells’ viability depends on the concentration and exposure time, and it has been demonstrated that PM1 exposure induces the release of the proinflammatory cytokines IL-6 and TNF-α by surrounding epithelial cells and macrophages ^[36]. This resulted in the upregulation of ICAM-1 on endothelial cells through the activation of TNF-α/NF-κB signalling pathways, which promotes the adhesion of monocytes to ECs, a key event in the initiation of atherosclerosis ^[36]. Similarly, Mo et al. ^[37] demonstrated that UFP exposure (10 and 20 μg/mL) resulted in IL-6 induction through the activation of p38 and ERK1/2 MAPKs. In this research, the researchers also demonstrated that these effects are caused by the induction of ROS, which occurs in a NAPDPH-oxidase-dependent manner ^[37].

By using tri-co-cultured systems consisting of alveolar epithelial cells, ECs and macrophages, Wang et al. ^[38] demonstrated that PM2.5 exposure induces a potent inflammatory response. In this research, EA.hy926 endothelial cells were not exposed to particulate matter directly, but different doses were chosen to study the mechanistic effects on both the cardiovascular and pulmonary system. Based on this methodology, it was possible to determine that the basolateral medium LDH that represents the cytotoxicity of EA.hy926, after PM2.5 exposure, did not induce significant EA.hy926 cytotoxicity, but the LDH levels were elevated meaningfully in high doses of PM2.5-treated apical co-cultures ^[38]. No reason was found for the different levels of LDH ^[39], but is known that its release into the extracellular space is a result of compromised or damaged cell membrane ^[39]. However, Bengalli et al. ^[40] found that exposure to PM10 increased IL-1β, a cytokine responsible for inflammatory responses on the cell ^[41], in ECs on the basolateral compartment; yet, no release in the apical compartment was observed, and it was not possible to find an explanation for that. The ABB (air–blood barrier) treated with CuO did not show a response in the basolateral compartment; this could be due to the integrity of the ABB which can inhibit the passage of CuO in the direction of the endothelial cells, while it enables to rise IL-6 and IL-8 release from the apical compartment ^[40]. Bengalli et al. ^[40] suggested that an explanation for CuO being free in the cytoplasm might be its higher oxidative potential compared with TiO2, and this can cause an oxidative degradation of lipids in vesicles, leaving CuO free. Exposure to PM10 and nanoparticles was shown to induce modulation in proinflammatory proteins and ECs ^[40].

2.2. Cigarette Smoke

It is established that CS interferes with the capacity of airway epithelial cells to uphold repair processes and also can lead to modifications in the airway structures and functions that characterise COPD ^[10]. It can cause detrimental cell responses, inducing tissue damage around the alveoli and airways, with the subjacent development of various lung diseases ^[42], such as lung cancer and asthma (9).

One of the molecular effects of e-smoking is the reduction in NO levels ^[43], and it is known that NO loss is a key event for endothelial dysfunction ^[44]^[45]. In this regard, it has been demonstrated that HPMVEC subjected to serum from regular e-cigarette smokers produce ROS and increase ICAM-1 expression, demonstrating endothelial activation and inflammation, which together represent the first step in signalling events that are conducive to the pathogenesis of numerous vascular disorders ^[43]. It seems that the activation of NADPH oxidase 2 is the origin of ROS production, as a decrease in ROS production following the pre-treatment of HPMVECs with the NADPH oxidase 2 inhibitor—apocynin—was observed ^[43]. Furthermore, it is known that NO reacts with ROS to create peroxynitrite, which triggers a cellular response that can lead to apoptosis and necrosis ^[39]^[41]. Indeed, it is known that CS induces the death of epithelial and endothelial lung cells through apoptosis ^[46]^[47]. Actually, both cultured and mouse-lung ECs exposed to CS exhibit pronounced apoptosis, which is accompanied by emphysema ^[48]. The mechanisms that seem to induce these effects are the activation of endoplasmic reticulum (ER) stress and autophagy with increased eIF2α signalling. Additionally, in those settings, FAK signalling, a prosurvival pathway, is inhibited through oxidative stress ^[48]. It is noteworthy to emphasise that the researcher points out that the induction of the unfolded protein response (UPR) (a response to ER stress) is not an injury but rather a compensatory mechanism to protect from lung EC injury through the induction of the apoptotic death of dysfunctional cells ^[48]. This suggestion was based on the observation that the evolution of lung EC apoptosis and emphysema was associated with the impairment of eIF2α signalling, which occurs when UPR is diminished ^[48].

The mechanism by which CS induces cell death seems not to be restricted to apoptosis, as Mizumura, K. et al. ^[46]^[49] revealed that chronic CS also induces the mitophagy of lung structural cells that ultimately leads to necroptosis, a caspase-independent form of regulated cell death ^[46]^[49]. This event occurs through the induction of acid sphingomyelinase and the accumulation of the ceramide C16-Cer in a PINK1-dependent manner ^[49]. It is known that both apoptosis and necroptosis might contribute to the pathogenesis of COPD, particularly to its emphysema phenotype.

Epithelial and ECs form an important barrier in the alveolus, forming a semi-permeable interface for gas exchange that prevents alveolar and interstitial oedema formation ^[50]^[51]. A study by Schweitzer, K.S. et al. ^[52] demonstrated that CS exposure induces the disruption of the endothelial cell barrier. From a mechanistic point of view, CS induces the upregulation of neutral sphingomyelinase-mediated ceramide and p38 MAPK and JNK activation in addition to oxidative stress and Rho activation. Neutral sphingomyelinase activation is responsible for the observed morphological changes upon CS exposure, as it induces actin cytoskeletal rearrangement, junctional protein zonula occludens-1 loss and intercellular gap formation ^[52]. Schweitzer et al. ^[52] referred to the importance of the development of CS-induced emphysema because it is believed that oxidative stress and ceramides, which also have a role in regulating apoptosis ^[53], are involved in the emphysema pathogenesis. This mechanism may make endothelial cells more sensible to effects of subsequent injuries associated with ARDS which can evolve to chronic inflammatory changes associated with COPD ^[52].

2.3. Diesel Particles

As cited before, DEPs are a mixture of solid and liquid material that easily penetrate human lungs ^[14], being able to damage endothelial and fibrinolytic functions, stimulate blood thrombogenicity and intensify the gravity of cardiac ischemia in humans ^[54]. Regarding diesel particles, which are an ensemble of compounds, extremely dependent on fuel and engine, and have physical–chemical characteristics, studies about their effects often use standard reference materials (SRMs), and according to the results, DEPs are constituted of ultrafine particles and a tendency toward aggregation ^[55]. Regarding the DEPs tested by Bengalli et al. (2017) ^[56], SRMs were developed under controlled conditions (SRM, 1650b), being related to the emission of a heavy engine and a light engine (SRM, 2975). The chemical speciation of the EuroIV (light duty engine—types of vehicles that are under the emission limit, defined in Directive 98/69/EC) revealed a common PAH composition with elevated levels of phenanthrene, pyrene, dibenzo(a,h) anthracene and benzo[a]anthracene ^[55]. A series of events that linked UFP exposure to inflammation and oxidative stress with the consequential indirect activation of the vascular endothelium ^[55] and the release of VEGF from BEAS-2B ^[55] has been demonstrated. The risk of exposure on endothelial cells by PAHs is related to the fact that due to its activation, it can affect DNA, forming DNA adducts, leading to deletions, translocations, fusions or aneuploidy ^[57] through the formation of phenols, catechols, diol-epoxides, quinones, o-quinones and radical cations, which occurs during that formation ^[58]^[59]^[60].

The availability of IL-6R in BEAS-2B supernatants was assessed, revealing its overexpression after diesel exposure ^[56]. With the exposure of EURO IV, an increased expression of ICAM-1 and VCAM-1 was also visible, and also, the release of proinflammatory mediators (IL-6), which was also reported by Bengalli et al. ^[56]. The diesel-induced overexpression of ICAM-1 and VCAM-1 was successfully inhibited by interfering with IL-6/gp130 binding by the addition of an IL-6 antibody to epithelial cell media to reveal the important role of IL-6 released by epithelial cells in inducing the observed effects on endothelial cells ^[56].

2.4. Carbon Black

Finally, only one study selected tried to identify the relation between carbon black and its effects on endothelial cells. As previously stated, CB is mainly used as a black pigment, and individuals’ exposure to it occurs in industries. Based on Dinmohammadi et al. ^[61], the interaction poorly contributes to prothrombotic and proinflammatory effects during the cells’ exposure, as shown by unclear evidence.

Both FVIII and VWF are storage proteins in the endothelium which are released once stimulated by other exogenous or endogenous molecules ^[61], mediating platelet adhesion (Peyvandi et al., 2011), which binds to injured areas (Packham et al., 1984). FVIII has a role in the coagulation cascade ^[62] and is synthetised in endothelial cells ^[63]; the researchers previously observed an increase in FVIII in cardiac microvascular endothelial cells once exposed to UFPs and measured the same protein in HPMECs once exposed to CB, but no results were visible. VWF is also a protein that can be found in endothelial cells, linked to haemostasis, by binding to FVIII ^[64]. The protein P-selectin can be also found on the surface of platelets and endothelial cells once it is activated ^[65], influencing the regulation of platelet function ^[66]. Finally, IL-8, which is a cytokine which is produced by different cells and is linked with inflammation ^[67], has been associated with a direct role in the survival, proliferation and angiogenesis of endothelial cells ^[68].

These findings showed that no changes occurred in Weibel–Palade bodies (WPBs), which store all these proteins ^[69], are involved in inflammation ^[64]^[70]^[71] as inflammation mediators and are also linked to coagulation factors ^[69]. Since there was no response from endothelial cells to the UFPs and no increases in these proteins, this research ^[61] concluded that exposure did not contribute to prothrombotic and proinflammatory effects.

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