Nasal Epithelial Injury Research Articles

Ferroptosis is involved in PM2.5-induced acute nasal epithelial injury via AMPK-mediated autophagy.

PM2.5 is one of the main harmful environmental pollutants and can damage nasal epithelial carriers to worsen allergic rhinitis. Ferroptosis is a novel form of regulated cell death with iron-dependent lipid peroxidation. However, whether ferroptosis is involved in PM2.5-induced nasal epithelial injury has not been elucidated. To verify the vital role of ferroptosis in PM2.5-induced nasal epithelial injury and further explore the potential mechanism, we detected intracellular iron content, ROS release and lipid peroxidation and ferroptosis-related proteins in vitro as well as the pathological changes in the nasal epithelium and the levels of proinflammatory factors in nasal lavage fluid in vivo. Our results showed that PM2.5 exposure led to oxidative stress, labile iron accumulation and lipid peroxidation in HNEPCs. In addition, the expression levels of xCT, GPx4, FTH1 and FTL in HNEPCs were greatly inhibited by PM2.5. Treatment with the ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1) significantly reversed the toxicity of PM2.5 to human nasal epithelial cells (HNEPCs). Mechanistically, AMPK-mediated autophagy was initiated during PM2.5 exposure, which drove ferroptosis of HNEPCs. Autophagy inhibitor remarkably improved cell death, oxidative stress, labile iron accumulation, lipid peroxidation, and the downregulated expression of xCT, GPx4, FTH1 and FTL in HNEPCs induced by PM2.5. Furthermore, an AMPK inhibitor (Compound C, CC) and siRNA-AMPKα suppressed autophagy activation and ferroptosis stimulated by PM2.5. In vivo, Fer-1 reduced nasal epithelial injury and mucus secretion in PM2.5-exposed mice. In addition, CC significantly improved nasal epithelial damage and proinflammatory factor production in mice caused by PM2.5 intranasal treatment. In addition, CC greatly inhibited autophagy activation but reversed the downregulation of GPX4 and FTH1 induced by PM2.5 in the nasal epithelium of mice. Together, these data suggest that AMPK-mediated autophagy plays an important role in PM2.5-induced ferroptosis and that AMPK might be a potential treatment target for PM2.5-induced nasal epithelial injury.

Streptococcus agalactiae Infects Glial Cells and Invades the Central Nervous System via the Olfactory and Trigeminal Nerves.

Streptococcus agalactiae causes neonatal meningitis and can also infect the adult central nervous system (CNS). S. agalactiae can cross the blood-brain barrier but may also reach the CNS via other paths. Several species of bacteria can directly invade the CNS via the olfactory and trigeminal nerves, which extend between the nasal cavity and brain and injury to the nasal epithelium can increase the risk/severity of infection. Preterm birth is associated with increased risk of S. agalactiae infection and with nasogastric tube feeding. The tubes, also used in adults, can cause nasal injuries and may be contaminated with bacteria, including S. agalactiae. We here investigated whether S. agalactiae could invade the CNS after intranasal inoculation in mice. S. agalactiae rapidly infected the olfactory nerve and brain. Methimazole-mediated model of nasal epithelial injury led to increased bacterial load in these tissues, as well as trigeminal nerve infection. S. agalactiae infected and survived intracellularly in cultured olfactory/trigeminal nerve- and brain-derived glia, resulting in cytokine production, with some differences between glial types. Furthermore, a non-capsulated S. agalactiae was used to understand the role of capsule on glial cells interaction. Interestingly, we found that the S. agalactiae capsule significantly altered cytokine and chemokine responses and affected intracellular survival in trigeminal glia. In summary, this study shows that S. agalactiae can infect the CNS via the nose-to-brain path with increased load after epithelial injury, and that the bacteria can survive in glia.

Sulfur dioxide exposure reduces the quantity of CD19+ cells and causes nasal epithelial injury in rats

BackgroundReactive airway dysfunction syndrome (RADS), also called irritant-induced asthma, is a type of occupational asthma that can occur within a very short period of latency. The study sought to investigate the influence of sulfur dioxide (SO2) exposure on CD19+ cells and nasal epithelial injury.MethodsWe investigated the effects of SO2 on CD19 expression and morphological changes of nasal epithelia in rats. In the study, 20 rats were randomly divided into the SO2 exposure group that were exposed to 600 ppm SO2, 2 h/day for consecutive 7 days, and the control group that were exposed to filtered air).ResultsInhalation of high concentration of SO2significantly reduced CD19 expression at both the mRNA transcript and protein levels, and reduced the percentages of CD19+ cells and CD19+/CD23+ cells in the nasal septum. However, inhalation of high concentration of SO2 did not affect immunoglobulin (Ig) G, IgA and IgE levels in the serum and nasal septum. More importantly, SO2 exposure also caused mild structural changes of the nasal septum.ConclusionOur results reveal that inhalation of a high concentration of SO2 reduces CD19 expression and causes structural change of the nasal septum in rats.

Correlation Between Nasal Epithelial Injury and In Vitro Cytotoxicity Using a Series of Small Molecule Protein Tyrosine Phosphatase 1B Inhibitors Investigated for Reversal of Leptin Resistance in Obesity.

This research provides a cautionary example when evaluating changes in behavioral end points with respect to postulated pharmacologic activity. Various small molecule substrate mimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors were investigated as pharmacologic agents for decreasing food consumption using intranasal (IN) dosing as a means for direct nose-to-brain delivery along the olfactory/trigeminal nerve pathways. Although food consumption was decreased in diet-induced obese (DIO) mice, nasal discharge was observed. Studies were conducted to investigate local effects on the nasal airway and to develop structure-activity relationships. Intranasal administration of PTP1B inhibitors at ≥0.03 mg/d to DIO mice produced dose-dependent injury to various cell types of the nasal epithelia. Protein tyrosine phosphatase 1B inhibitors with calculated log octanol >3.0 were the most toxic. Whereas a pharmacologically inactive analog of a PTP1B inhibitor produced nasal injury, along with decreased food consumption, the marketed IN drug ketorolac produced no lesions at the same dose of 0.3 mg/d and only minor changes at 3 mg/d. Rat skin fibroblast cells were exposed in vitro to PTP1B inhibitors, ketorolac, paraquat, and the detergent sodium dodecylbenzene sulfonate (NDS) followed by measures of cytotoxicity. The most potent PTP1B inhibitors were similar to NDS, whereas ketorolac was the least toxic compound. Cytotoxic potency in vitro was similar to in vivo. In conclusion, PTP1B inhibitors injured nasal epithelium through a mechanism independent of PTP1B inhibition and likely due to nonspecific cytotoxicity such as disruption of the cell membrane. Decreased food consumption in DIO mice was due to toxicity rather than a pharmacologic mode of action.

Three-Dimensional Mapping of Ozone-Induced Injury in the Nasal Airways of Monkeys Using Magnetic Resonance Imaging and Morphometric Techniques

Age-related changes in gross and microscopic structure of the nasal cavity may alter local tissue susceptibility as well as the dose of inhaled toxicant delivered to susceptible sites. This article describes a novel method for the use of magnetic resonance imaging, 3-dimensional airway modeling, and morphometric techniques to characterize the distribution and magnitude of ozone-induced nasal injury in infant monkeys. Using this method, we generated age-specific, 3-dimensional, epithelial maps of the nasal airways of infant Rhesus macaques. The principal nasal lesions observed in this primate model of ozone-induced nasal toxicology were neutrophilic rhinitis, along with necrosis and exfoliation of the epithelium lining the anterior maxilloturbinate. These lesions, induced by acute or cyclic (episodic) exposures, were examined by light microscopy, quantified by morphometric techniques, and mapped on 3-dimensional models of the nasal airways. Here, we describe the histopathologic, imaging, and computational biology methods developed to precisely characterize, localize, quantify, and map these nasal lesions. By combining these techniques, the location and severity of the nasal epithelial injury were correlated with epithelial type, nasal airway geometry, and local biochemical and molecular changes on an individual animal basis. These correlations are critical for accurate predictive modeling of exposure-dose-response relationships in the nasal airways, and subsequent extrapolation of nasal findings in animals to humans for determining risk.

Characterization of upper respiratory disease in rats following neonatal inoculation with a rat-adapted influenza virus.

Neonatal F344 rats were infected with a rat-adapted influenza virus (RAIV) to use as a potential model to study the combined effects of air pollutant exposure with early life respiratory viral infections. Initially, 6-day-old pups were intranasally inoculated with RAIV or medium alone, and nasal and lower respiratory tract (LRT) tissues were assessed histologically at 1, 3, 6, and 13 days postinoculation (DPI). Immunologic assessments included thymic lymphocyte quantification and anti-RAIV immunoglobulin production. Pups then received two inoculations (at 6 and 30 days of age), with histologic and immunologic assessment 6 and 13 days after the second inoculation and bronchoprovocation testing 5-8 weeks later. Following the single RAIV inoculation, IgM and IgG1 measurements increased at 6, 11, and 15 DPI, with IgG1 being greater at 11 and 15 DPI. Nasal lesions were evident as early as 1 DPI and primarily involved the anterior dorsal medial meatus and adjacent dorsal atrio- and nasoturbinates. Alterations included epithelial cell exfoliation and necrosis, mild erosions, suppurative and nonsuppurative inflammation, intraepithelial neutrophil accumulations, and intraluminal exudate. By 3 DPI, olfactory epithelial damage was multifocal or locally diffuse, with degeneration of sensory cells and variable inflammation. By 13 DPI, lesions were essentially repaired. Minimal changes were apparent in the LRT despite evidence of viral replication in the lungs 24 hours after inoculation (> 3 log10 plaque-forming units/lung). Pups reinoculated with RAIV at 30 days of age did not develop significant histologic lesions, nor did they exhibit increased airway responsiveness when assessed as young adults. In spite of their immature immune status at the time of initial infection, 13 days after the second RAIV inoculation, IgG1 increased substantially. Thus, neonatal RAIV infection resulted in acute nasal epithelial injury and inflammation, alterations that may allow subsequent evaluation of viral disease-air pollutant interactions.

Effects of Ozone Combined with Components of Acid Fogs on Breathing Pattern, Metabolic Rate, Pulmonary Surfactant Composition, and Lung Injury in Rats

AbstractThe pulmonary responses to components of acid fogs, nitric acid, sulfuric acid, and hydroxymethanesulfonate (HMSA), in combination with ozone (O3) were measured to determine if the acid components altered the course of inflammatory responses to the oxidant. Rats were exposed 4 h to 0.4 ppm O3 0.4 ppm O3 + 0.7 mg/m3 HNO3 + 0.6 mg/m3 H2SO4 0.6 mg/m3 HMSA, and 0.4 ppm O3 + 0.5 mg/m3 HMSA. Breathing pattern and metabolic rate were measured during exposure, and fatty acid composition of pulmonary surfactant (PS), nasal epithelial injury, oxidant-induced lung parenchymal lesions, and changes in the total protein in the lavage fluids were measured 23–48 h postexposure. Ozone alone affected all measures except nasal epithelial injury, and the presence of inorganic acids or HMSA in combination with 0.4 ppm O3 did not significantly modify the response to O3 alone. The only response to 0.6 mg/m3 HMSA alone was depression in metabolic rate during exposure. The presence of a pulmonary irritant rapid-shallow br...

Effects of exercise exposure on toxic interactions between inhaled oxidant and aldehyde air pollutants.

Respiratory tract injury resulting from inhalation of mixtures of ozone (O3) and nitrogen dioxide (NO2) and of O3 and formaldehyde (HCHO) was studied in Sprague-Dawley rats under exposure conditions of rest and exercise. Focal inflammatory injury induced in lung parenchyma by O3 exposure was measured morphometrically and HCHO injury to the nasal respiratory epithelium was measured by cell turnover using tritium-labeled thymidine. Mixtures of O3 (0.35 or 0.6 ppm) with NO2 (respectively 0.6 or 2.5 ppm) doubled the level of lung injury produced by O3 alone in resting exposures to the higher concentrations and in exercising exposures to the lower concentrations. Formaldehyde (10 ppm) mixed with O3 (0.6 ppm) resulted in reduced lung injury compared to O3 alone in resting exposures, but exercise exposure to the mixture did not show an antagonistic interaction. Nasal epithelial injury from HCHO exposure was enhanced when O3 was present in a mixture. Mixtures of O3 and NO2 at high and low concentrations formed respectively 0.73 and 0.02 ppm nitric acid (HNO3) vapor. Chemical interactions among the oxidants, HNO3, and other reaction products (N2O5 and nitrate radical) and lung tissue may be the basis for the O3-NO2 synergism. Increased dose and dose rate associated with exercise exposure may explain the presence of synergistic interaction at lower concentrations than observed in resting exposure. No oxidation products were detected in O3-HCHO mixtures, and the antagonistic interaction observed in lung tissue during resting exposure may result from irritant breathing pattern interactions.