The role of ROS-pyroptosis in PM2.5 induced air-blood barrier destruction.

Fine particulate matter (PM2.5) has attracted increasing attention due to its health-threatening effects. Although numerous studies have investigated the impact of PM2.5 on lung injuries, the specific mechanisms underlying the damage to the air-blood barrier after exposure to PM2.5 remain unclear. In this study, we established an in vitro co-culture system using lung epithelial cells and capillary endothelial cells. Our findings indicated that the tight junction (TJ) proteins were up-regulated in the co-cultured system compared to the monolayer-cultured cells, suggesting the establishment of a more closely connected in vitro system. Following exposure to PM2.5, we observed damage to the air-blood barrier in vitro. Concurrently, PM2.5 exposure induced significant oxidative stress and activated the NLRP3 inflammasome-mediated pyroptosis pathway. When oxidative stress was inhibited, we observed a decrease in pyroptosis and an increase in TJ protein levels. Additionally, disulfiram reversed the adverse effects of PM2.5, effectively suppressing pyroptosis and ameliorating air-blood barrier dysfunction. Our results indicate that the oxidative stress-pyroptosis pathway plays a critical role in the disruption of the air-blood barrier induced by PM2.5 exposure. Disulfiram may represent a promising therapeutic option for mitigating PM2.5-related lung damage.

Chronic heat stress induces lung injury in broiler chickens by disrupting the pulmonary blood-air barrier and activating TLRs/NF-κB signaling pathway.

As an important respiratory organ, the lung is susceptible to damage during heat stress due to the accelerated breathing frequency caused by an increase in environmental temperature. This can affect the growth performance of animals and endanger their health. This study aimed to explore the mechanism of lung tissue damage caused by heat stress. Broilers were randomly divided into a control group (Control) and a heat stress group (HS). The HS group was exposed to 35°C heat stress for 12 h per d from 21-days old, and samples were taken from selected broilers at 28, 35, and 42-days old. The results showed a significant increase in lactate dehydrogenase (LDH) activity in the serum and myeloperoxidase (MPO) activity in the lungs of broiler chickens across all 3 age groups after heat stress (P < 0.01), while the total antioxidant capacity (T-AOC) was significantly enhanced at 35-days old (P < 0.01). Heat stress also led to significant increases in various proinflammatory factors in serum and expression levels of HSP60 and HSP70 in lung tissue. Histopathological results showed congestion and bleeding in lung blood vessels, shedding of pulmonary epithelial cells, and a large amount of inflammatory infiltration in the lungs after heat stress. The mRNA expression of TLRs/NF-κB-related genes showed an upward trend (P < 0.05) after heat stress, while the mRNA expression of MLCK, a gene related to pulmonary blood-air barrier, significantly increased after heat stress, and the expression levels of MLC, ZO-1, and occludin decreased in contrast. This change was also confirmed by Western blotting, indicating that the pulmonary blood-air barrier is damaged after heat stress. Heat stress can cause damage to the lung tissue of broiler chickens by disrupting the integrity of the blood-air barrier and increasing permeability. This effect is further augmented by the activation of TLRs/NF-κB signaling pathways leading to an intensified inflammatory response. As heat stress duration progresses, broiler chickens develop thermotolerance, which gradually mitigates the damaging effects induced by heat stress.

Oxypeucedanin relieves LPS-induced acute lung injury by inhibiting the inflammation and maintaining the integrity of the lung air-blood barrier.

INTRODUCTION: Acute lung injury (ALI) is commonly accompanied by a severe inflammatory reaction process, and effectively managing inflammatory reactions is an important therapeutic approach for alleviating ALI. Macrophages play an important role in the inflammatory response, and this role is proinflammatory in the early stages of inflammation and anti-inflammatory in the late stages. Oxypeucedanin is a natural product with a wide range of pharmacological functions. This study aimed to determine the effect of oxypeucedanin on lipopolysaccharide (LPS)-induced ALI. METHODS AND RESULTS: In this study, the following experiments were performed based on LPS-induced models in vivo and in vitro. Using myeloperoxidase activity measurement, ELISA, qRT-PCR, and Western blotting, we found that oxypeucedanin modulated the activity of myeloperoxidase and decreased the expression levels of inflammatory mediators such as TNF-α, IL-6, IL-1ß, MPO, COX-2 and iNOS in LPS-induced inflammation models. Meanwhile, oxypeucedanin inhibited the activation of PI3K/AKT and its downstream NF-κB and MAPK signaling pathways. In addition, oxypeucedanin significantly decreased the pulmonary vascular permeability, which was induced by LPSs, and the enhanced expression of tight junction proteins (Occludin and Claudin 3). CONCLUSIONS: In conclusion, this study demonstrated that the anti-inflammatory mechanism of oxypeucedanin is associated with the inhibition of the activation of PI3K/AKT/NF-κB and MAPK signaling pathways and the maintenance of the integrity of the lung air-blood barrier.

Pyroptosis participates in PM2.5-induced air-blood barrier dysfunction.

Epidemiological studies have shown that particulate matters with diameter less than 2.5 µm (PM2.5) play an important role in inducing and promoting respiratory diseases, but its underlying mechanism remains to be explored. The air-blood barrier, also known as the alveolar-capillary barrier, is the key element of the lung, working as the site of oxygen and carbon dioxide exchange between pulmonary vasculatures. In this study, a mouse PM2.5 exposure model was established, which leads to an induced lung injury and air-blood barrier disruption. Oxidative stress and pyroptosis were observed in this process. After reducing the oxidative stress by N-acetyl-L-cysteine (NAC) treatment, the air-blood barrier function was improved and the effect of PM2.5 was alleviated. The level of pyroptosis and related pathway were also effectively relieved. These results indicate that acute PM2.5 exposure can cause lung injury and the alveolar-capillary barrier disruption by inducing reactive oxygen species (ROS) with the participation of pyroptosis pathway.

The blood-gas barrier in COVID-19: an overview of the effects of SARS-CoV-2 infection on the alveolar epithelial and endothelial cells of the lung.

Blood-gas barrier (BGB) or alveolar-capillary barrier is the primary tissue barrier affected by coronavirus disease 2019 (COVID-19). Comprising alveolar epithelial cells (AECs), endothelial cells (ECs) and the extracellular matrix (ECM) in between, the BGB is damaged following the action of multiple pro-inflammatory cytokines during acute inflammation. The infection of AECs and ECs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen behind COVID-19, triggers an inflammatory response at the BGB, inducing the release of interleukin 1 (IL-1), IL-6, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-ß), high mobility group box 1 (HMGB1), matrix metalloproteinases (MMPs), intercellular adhesion molecule-1 (ICAM-1) and platelet activating factor (PAF). The end result is the disassembly of adherens junctions (AJs) and tight junctions (TJs) in both AECs and ECs, AEC hyperplasia, EC pyroptosis, ECM remodeling and deposition of fibrin clots in the alveolar capillaries, leading to disintegration and thickening of the BGB, and ultimately, hypoxia. This commentary seeks to provide a brief account of how the BGB might become affected in COVID-19.

Effect of Alpha-1 Antitrypsin on CFTR Levels in Primary Human Airway Epithelial Cells Grown at the Air-Liquid-Interface.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene is influenced by the fundamental cellular processes like epithelial differentiation/polarization, regeneration and epithelial-mesenchymal transition. Defects in CFTR protein levels and/or function lead to decreased airway surface liquid layer facilitating microbial colonization and inflammation. The SERPINA1 gene, encoding alpha1-antitrypsin (AAT) protein, is one of the genes implicated in CF, however it remains unknown whether AAT has any influence on CFTR levels. In this study we assessed CFTR protein levels in primary human lung epithelial cells grown at the air-liquid-interface (ALI) alone or pre-incubated with AAT by Western blots and immunohistochemistry. Histological analysis of ALI inserts revealed CFTR- and AAT-positive cells but no AAT-CFTR co-localization. When 0.5 mg/mL of AAT was added to apical or basolateral compartments of pro-inflammatory activated ALI cultures, CFTR levels increased relative to activated ALIs. This finding suggests that AAT is CFTR-modulating protein, albeit its effects may depend on the concentration and the route of administration. Human lung epithelial ALI cultures provide a useful tool for studies in detail how AAT or other pharmaceuticals affect the levels and activity of CFTR.

Ruscogenin attenuates sepsis-induced acute lung injury and pulmonary endothelial barrier dysfunction via TLR4/Src/p120-catenin/VE-cadherin signalling pathway.

OBJECTIVES: Sepsis-associated acute lung injury (ALI) occurs with the highest morbidity and carries the highest mortality rates among the pathogenies of ALI. Ruscogenin (RUS) has been found to exhibit anti-inflammation property and rescue lipopolysaccharide-induced ALI, but little is known about its role in sepsis-triggered ALI. The aim of this study was to investigate the potential role of RUS in sepsis-induced ALI and the probable mechanism. METHODS: Mice model of cecal ligation and puncture (CLP) was replicated, and three doses of RUS (0.01, 0.03 and 0.1 mg/kg) were administrated 1 h before CLP surgeries. KEY FINDINGS: RUS significantly extended the survival time and attenuated the lung pathological injury, oedema and vascular leakage in sepsis-induced ALI mice. RUS efficiently decreased the level of MPO in lung tissue and the WBC, NEU counts in BALF. In addition, RUS rescued the expression of VE-cadherin and p120-catenin and suppressed the TLR4/Src signalling in lung tissue. CONCLUSIONS: RUS attenuated sepsis-induced ALI via protecting pulmonary endothelial barrier and regulating TLR4/Src/p120-catenin/VE-cadherin signalling pathway.

Investigation of the MSC Paracrine Effects on Alveolar-Capillary Barrier Integrity in the In Vitro Models of ARDS.

Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical disorder with high mortality rates and no specific pharmacological treatment available yet. It is characterized by excessive inflammation in the alveolar compartment resulting in edema of the airspaces due to loss of integrity in the alveolar epithelial-endothelial barrier leading to the development of hypoxemia and often severe respiratory failure. Changes in the permeability of the alveolar epithelial-endothelial barrier contribute to excessive inflammation, the formation of lung edema and impairment of the alveolar fluid clearance. In recent years, Mesenchymal Stromal Cells (MSCs) have attracted attention as a cell therapy for ARDS. MSCs are known to secrete a variety of biologically active factors (growth factors, cytokines, and extracellular vesicles). These paracrine factors have been shown to be major effectors of the anti-inflammatory and regenerative properties observed in multiple in vitro and in vivo studies. This chapter provides a simple protocol on how to investigate the paracrine effect of MSCs on the alveolar epithelial-endothelial barrier functions.

Purinergic Regulation of Endothelial Barrier Function.

Increased vascular permeability is a hallmark of several cardiovascular anomalies, including ischaemia/reperfusion injury and inflammation. During both ischaemia/reperfusion and inflammation, massive amounts of various nucleotides, particularly adenosine 5'-triphosphate (ATP) and adenosine, are released that can induce a plethora of signalling pathways via activation of several purinergic receptors and may affect endothelial barrier properties. The nature of the effects on endothelial barrier function may depend on the prevalence and type of purinergic receptors activated in a particular tissue. In this review, we discuss the influence of the activation of various purinergic receptors and downstream signalling pathways on vascular permeability during pathological conditions.

Mechanical ventilation-induced alterations of intracellular surfactant pool and blood-gas barrier in healthy and pre-injured lungs.

Mechanical ventilation triggers the manifestation of lung injury and pre-injured lungs are more susceptible. Ventilation-induced abnormalities of alveolar surfactant are involved in injury progression. The effects of mechanical ventilation on the surfactant system might be different in healthy compared to pre-injured lungs. In the present study, we investigated the effects of different positive end-expiratory pressure (PEEP) ventilations on the structure of the blood-gas barrier, the ultrastructure of alveolar epithelial type II (AE2) cells and the intracellular surfactant pool (= lamellar bodies, LB). Rats were randomized into bleomycin-pre-injured or healthy control groups. One day later, rats were either not ventilated, or ventilated with PEEP = 1 or 5 cmH2O and a tidal volume of 10 ml/kg bodyweight for 3 h. Left lungs were subjected to design-based stereology, right lungs to measurements of surfactant proteins (SP-) B and C expression. In pre-injured lungs without ventilation, the expression of SP-C was reduced by bleomycin; while, there were fewer and larger LB compared to healthy lungs. PEEP = 1 cmH2O ventilation of bleomycin-injured lungs was linked with the thickest blood-gas barrier due to increased septal interstitial volumes. In healthy lungs, increasing PEEP levels reduced mean AE2 cell size and volume of LB per AE2 cell; while in pre-injured lungs, volumes of AE2 cells and LB per cell remained stable across PEEPs. Instead, in pre-injured lungs, increasing PEEP levels increased the number and decreased the mean size of LB. In conclusion, mechanical ventilation-induced alterations in LB ultrastructure differ between healthy and pre-injured lungs. PEEP = 1 cmH2O but not PEEP = 5 cmH2O ventilation aggravated septal interstitial abnormalities after bleomycin challenge.

Alveolar epithelial glycocalyx shedding aggravates the epithelial barrier and disrupts epithelial tight junctions in acute respiratory distress syndrome.

The main pathophysiological mechanism of acute respiratory distress syndrome (ARDS) invovles the increase in alveolar barrier permeability that is primarily caused by epithelial glycocalyx and tight junction (TJ) protein destruction. This study was performed to explore the effects of the alveolar epithelial glycocalyx on the epithelial barrier, specifically on TJ proteins, in ARDS. We used C57BL/6 mice and human lung epithelial cell models of lipopolysaccharide (LPS)-induced ARDS. Changes in alveolar permeability were evaluated via pulmonary histopathology analysis and by measuring the wet/dry weight ratio of the lungs. Degradation of heparan sulfate (HS), an important component of the epithelial glycocalyx, and alterations in levels of the epithelial TJ proteins (occludin, zonula occludens 1, and claudin 4) were assessed via ELISA, immunofluorescence analysis, and western blotting analysis. Real-time quantitative polymerase chain reaction was used to detect the mRNA of the TJ protein. Changes in glycocalyx and TJ ultrastructures in alveolar epithelial cells were evaluated through electron microscopy. In vivo and in vitro, LPS increased the alveolar permeability and led to HS degradation and TJ damage. After LPS stimulation, the expression of the HS-degrading enzyme heparanase (HPA) in the alveolar epithelial cells was increased. The HPA inhibitor N-desulfated/re-N-acetylated heparin alleviated LPS-induced HS degradation and reduced TJ damage. In vitro, recombinant HPA reduced the expression of the TJ protein zonula occludens-1 (ZO-1) and inhibited its mRNA expression in the alveolar epithelial cells. Taken together, our results demonstrate that shedding of the alveolar epithelial glycocalyx aggravates the epithelial barrier and damages epithelial TJ proteins in ARDS, with the underlying mechanism involving the effect of HPA on ZO-1.

Acetylharpagide Protects Mice from Staphylococcus Aureus-Induced Acute Lung Injury by Inhibiting NF-κB Signaling Pathway.

Staphylococcus aureus (S. aureus)-induced acute lung injury (ALI) is a serious disease that has a high risk of death among infants and teenagers. Acetylharpagide, a natural compound of Ajuga decumbens Thunb. (family Labiatae), has been found to have anti-tumor, anti-inflammatory and anti-viral effects. This study investigates the therapeutic effects of acetylharpagide on S. aureus-induced ALI in mice. Here, we found that acetylharpagide alleviated S. aureus-induced lung pathological morphology damage, protected the pulmonary blood-gas barrier and improved the survival of S. aureus-infected mice. Furthermore, S. aureus-induced myeloperoxidase (MPO) activity of lung homogenate and pro-inflammatory factors in bronchoalveolar lavage (BAL) fluid were suppressed by acetylharpagide. Mechanically, acetylharpagide inhibited the interaction between polyubiquitinated receptor interacting protein 1 (RIP1) and NF-κB essential modulator (NEMO), thereby suppressing NF-κB activity. In summary, these results show that acetylharpagide protects mice from S. aureus-induced ALI by suppressing the NF-κB signaling pathway. Acetylharpagide is expected to become a potential treatment for S. aureus-induced ALI.

Gold nanoparticles disrupt actin organization and pulmonary endothelial barriers.

This study explored the impact of gold nanoparticles on the metabolic activity and morphology of human pulmonary endothelial cell monolayers. We developed a gold nanoparticle library of three different sizes and two surface chemistries that include anionic citrate and the cationic polyelectrolyte poly(allylamine hydrochloride). The nanoparticles were characterized in cell culture medium to assess how their physical properties are altered after exposure to biological fluids. A bovine serum albumin pretreatment protocol was developed to stabilize the nanoparticles in cell culture medium. Results of this study show that an 18 h exposure of human pulmonary artery endothelial cells to the different nanoparticles modestly affects cellular metabolic activity. However, nanoparticle exposure perturbs the cortical actin networks and induces the formation of intercellular gaps. In particular, exposure to the poly(allylamine hydrochloride)-coated particles reduces the area of cell-cell junctions-a change that correlates with increased leakiness of endothelial barriers. The presence of excess polyelectrolyte capping agents in the supernatant of poly(allylamine hydrochloride)-coated nanoparticles significantly impacts endothelial morphology. Pretreatment of the particle supernatant with bovine serum albumin mitigates the negative effects of free or bound polyelectrolytes on endothelial cell monolayers.

Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation.

Increased permeability of vascular lung tissues is a hallmark of acute lung injury and is often caused by edemagenic insults resulting in inflammation. Vascular endothelial (VE)-cadherin undergoes internalization in response to inflammatory stimuli and is recycled at cell adhesion junctions during endothelial barrier re-establishment. Here, we hypothesized that phospholipase D (PLD)-generated phosphatidic acid (PA) signaling regulates VE-cadherin recycling and promotes endothelial barrier recovery by dephosphorylating VE-cadherin. Genetic deletion of PLD2 impaired recovery from protease-activated receptor-1-activating peptide (PAR-1-AP)-induced lung vascular permeability and potentiated inflammation in vivo In human lung microvascular endothelial cells (HLMVECs), inhibition or deletion of PLD2, but not of PLD1, delayed endothelial barrier recovery after thrombin stimulation. Thrombin stimulation of HLMVECs increased co-localization of PLD2-generated PA and VE-cadherin at cell-cell adhesion junctions. Inhibition of PLD2 activity resulted in prolonged phosphorylation of Tyr-658 in VE-cadherin during the recovery phase 3 h post-thrombin challenge. Immunoprecipitation experiments revealed that after HLMVECs are thrombin stimulated, PLD2, VE-cadherin, and protein-tyrosine phosphatase nonreceptor type 14 (PTPN14), a PLD2-dependent protein-tyrosine phosphatase, strongly associate with each other. PTPN14 depletion delayed VE-cadherin dephosphorylation, reannealing of adherens junctions, and barrier function recovery. PLD2 inhibition attenuated PTPN14 activity and reversed PTPN14-dependent VE-cadherin dephosphorylation after thrombin stimulation. Our findings indicate that PLD2 promotes PTPN14-mediated dephosphorylation of VE-cadherin and that redistribution of VE-cadherin at adherens junctions is essential for recovery of endothelial barrier function after an edemagenic insult.

Myofibroblast contraction is essential for generating and regenerating the gas-exchange surface.

A majority (~95%) of the gas-exchange surface area is generated through septa formation during alveologenesis. Disruption of this process leads to alveolar simplification and bronchopulmonary dysplasia (BPD), a prevalent disorder in premature infants. Although several models have been proposed, the mechanism of septa formation remains under debate. Here we show that inactivation of myosin light chain kinase (MLCK), a key factor required for myofibroblast contraction, disrupted septa formation, supporting the myofibroblast contraction model of alveologenesis. The alveoli simplification phenotype was accompanied by decreased yes-associated protein (YAP), a key effector in the Hippo mechanotransduction pathway. Expression of activated YAP in Mlck-mutant lungs led to partial reversal of alveolar simplification. In the adult, although Mlck inactivation did not lead to simplification, it prevented reseptation during compensatory regrowth in the pneumonectomy model. These findings revealed that myofibroblast reactivation and contraction are requisite steps toward regenerating the gas-exchange surface in diseases such as BPD and chronic obstructive pulmonary disease (COPD).

Brain Distributional Kinetics of a Novel MDM2 Inhibitor SAR405838: Implications for Use in Brain Tumor Therapy.

Achieving an effective drug concentration in the brain is as important as targeting the right pathway when developing targeted agents for brain tumors. SAR405838 is a novel molecularly targeted agent that is in clinical trials for various solid tumors. Its application for tumors in the brain has not yet been examined, even though the target, the MDM2-p53 interaction, is attractive for tumors that could occur in the brain, including glioblastoma and brain metastases. In vitro and in vivo studies indicate that SAR405838 is a substrate of P-glycoprotein (P-gp). P-gp mediated active efflux at the blood-brain barrier plays a dominant role in limiting SAR405838 brain distribution. Even though the absence of P-gp significantly increases the drug exposure in the brain, the systemic exposure, including absorption and clearance processes, were unaffected by P-gp deletion. Model-based parameters of SAR405838 distribution across the blood-brain barrier indicate the CLout of the brain was approximately 40-fold greater than the CLin The free fraction of SAR405838 in plasma and brain were found to be low, and subsequent Kpuu values were less than unity, even in P-gp/Bcrp knockout mice. These results indicate additional efflux transporters other than P-gp and Bcrp may be limiting distribution of SAR405838 to the brain. Concomitant administration of elacridar significantly increased brain exposure, also without affecting the systemic exposure. This study characterized the brain distributional kinetics of SAR405838, a novel MDM2 inhibitor, to evaluate its potential in the treatment of primary and metastatic brain tumors. SIGNIFICANCE STATEMENT: This paper examined the brain distributional kinetics of a novel MDM2-p53 targeted agent, SAR405838, to see its possible application for brain tumors by using in vitro, in vivo, and in silico approaches. SAR405838 is found to be a substrate of P-glycoprotein (P-gp), which limits its distribution to the brain. Based on the findings in the paper, manipulation of the function of P-gp can significantly increase the brain exposure of SAR405838, which may give an insight on its potential benefit as a treatment for primary and metastatic brain cancer.

Comparative Toxicity of Nanomaterials to Air-blood Barrier Permeability Using an In Vitro Model.

OBJECTIVE: To comparatively study the toxicity of four metal-containing nanoparticles (MNPs) and their chemical counterparts to the air-blood barrier (ABB) permeability using an in vitro model. METHODS: ABB model, which was developed via the co-culturing of A549 and pulmonary capillary endothelium, was exposed to spherical CuO-NPs (divided into CuO-40, CuO-80, and CuO-100 based on particle size), nano-Al2O3 (sheet and short-rod-shaped), nano-ZnO, nano-PbS, CuSO4, Al2(SO4)3, Zn(CH3COO)2, and Pb(NO3)2 for 60 min. Every 10 min following exposure, the cumulative cleared volume (ΔTCL) of Lucifer yellow by the model was calculated. A clearance curve was established using linear regression analysis of ΔTCL versus time. Permeability coefficient (P) was calculated based on the slope of the curve to represent the degree of change in the ABB permeability. RESULTS: The results found the increased P values of CuO-40, CuO-80, sheet, and short-rod-shaped nano-Al2O3, Al2(SO4)3, and Pb(NO3)2. Among them, small CuO-40 and CuO-80 were stronger than CuO-100 and CuSO4; no difference was observed between Al2(SO4)3 and sheet and short-rod-shaped nano-Al2O3; and nano-PbS was slightly weaker than Pb(NO3)2. So clearly the MNPs possess diverse toxicity. CONCLUSION: ABB permeability abnormality means pulmonary toxicity potential. More studies are warranted to understand MNPs toxicity and ultimately control the health hazards.

Age-Dependent Translocation of Gold Nanoparticles across the Air-Blood Barrier.

Do immature lungs have air-blood barriers that are more permeable to inhaled nanoparticles than those of fully developed mature lungs? Data supporting this notion and explaining the underlying mechanisms do not exist as far as we know. Using a rat model of postnatal lung development, here the data exactly supporting this notion, that is, significantly more gold nanoparticles (NPs) cross from the air space of the lungs to the rest of the body in neonates than in adults, are presented. Moreover, in neonates the translocation of gold NPs is not size dependent, whereas in adult animals smaller NPs cross the air-blood lung barrier much more efficiently than larger NPs. This difference in air-blood permeability in neonate versus adult animals suggests that NP translocation in the immature lungs may follow different rules than in mature lungs. Supporting this notion, we propose that the paracellular transport route may play a more significant role in NP translocation in immature animals, as suggested by protein expression studies. Findings from this study are critical to design optimal ways of inhalation drug delivery using NP nanocarriers for this age group, as well as for better understanding of the potential adverse health effects of nanoparticle exposures in infants and young children.

Cigarette Smoke Induced Lung Barrier Dysfunction, EMT, and Tissue Remodeling: A Possible Link between COPD and Lung Cancer.

Chronic obstructive pulmonary disease (COPD) and lung cancer, closely related to smoking, are major lung diseases affecting millions of individuals worldwide. The generated gas mixture of smoking is proved to contain about 4,500 components such as carbon monoxide, nicotine, oxidants, fine particulate matter, and aldehydes. These components were considered to be the principle factor driving the pathogenesis and progression of pulmonary disease. A large proportion of lung cancer patients showed a history of COPD, which demonstrated that there might be a close relationship between COPD and lung cancer. In the early stages of smoking, lung barrier provoked protective response and DNA repair are likely to suppress these changes to a certain extent. In the presence of long-term smoking exposure, these mechanisms seem to be malfunctioned and lead to disease progression. The infiltration of inflammatory cells to mucosa, submucosa, and glandular tissue caused by inhaled cigarette smoke is responsible for the destruction of matrix, blood supply shortage, and epithelial cell death. Conversely, cancer cells have the capacity to modulate the proliferation of epithelial cells and produce of new vascular networks. Comprehension understanding of mechanisms responsible for both pathologies is necessary for the prevention and treatment of COPD and lung cancer. In this review, we will summarize related articles and give a glance of possible mechanism between cigarette smoking induced COPD and lung cancer.