Response Of Respiratory Tract Research Articles

Correlation of dietary flavonoid intake with chronic bronchitis, emphysema, and asthma in U.S. adults: A large, national, cross-sectional study.

To explore the relationship between dietary flavonoids and bronchitis, emphysema and asthma. A total of 11743 United States adults were extracted from the National Health and Nutrition Examination Survey (NHANES) in 2007-2008, 2009-2010 and 2017-2018. Of these, 47.7% were male and 52.3% female. Dietary flavonoid intake assessed using FDNNS and 24-hour dietary recall data. Inclusion of demographics (gender, age, education, family income), behavioral factors (BMI, smoking, drinking status, diet), chronic disease information (diabetes, hypertension) as covariates to eliminate confounding. Stepwise logistic regression was used to analyze the association between total dietary flavonoid intake and the risk of chronic respiratory disease. Weighted quantile sum regression (WQS) was used to analyze the association between 29 dietary flavonoids and the risk of chronic respiratory disease. Restricted cubic spline was used to analyze the dose-response relationship between dietary flavonoid intake and risk of chronic respiratory disease. Stepwise logistic regression results showed that higher flavonoid intake in men was associated with a lower risk of CB and asthma (OR of CB: 0.55(0.31-0.97); OR of asthma: 0.72(0.52-0.99)), and WQS results showed a mixed health effect for total flavonoids and chronic respiratory tract in response to the 29 flavonoid fractions (OR of asthma: 0.97(0.94-0.99); OR of emphysema: 0.95(0.90-0.99)). Glycitein had the highest health contribution of 26.2% for emphysema; Eriodictyol had the highest health contribution of 32.13% for asthma, respectively. The RCS showed a dose-response relationship between flavonoids and respiratory tract health. The maximum dose for ingesting flavonoids to gain respiratory health benefits is 1500 mg/d. Higher dietary flavonoid intake was associated with lower chronic respiratory risk in adult U.S. men. Also 29 dietary flavonoid components have an overall health effect on respiratory health. Glycitein and Eriodictyol may have potential health effects on the respiratory system. 1500 mg/day may be the Tolerable Upper Intake Level of dietary flavonoids for respiratory health in U.S. adults.

Does early life exposure to exogenous sources of reactive oxygen species (ROS) increase the risk of respiratory and allergic diseases in children? A longitudinal cohort study

BackgroundExcess reactive oxygen species (ROS) can cause oxidative stress damaging cells and tissues, leading to adverse health effects in the respiratory tract. Yet, few human epidemiological studies have quantified the adverse effect of early life exposure to ROS on child health. Thus, this study aimed to examine the association of levels of ROS exposure at birth and the subsequent risk of developing common respiratory and allergic diseases in children.Methods1,284 Toronto Child Health Evaluation Questionnaire (T-CHEQ) participants were followed from birth (born between 1996 and 2000) until outcome, March 31, 2016 or loss-to-follow-up. Using ROS data from air monitoring campaigns and land use data in Toronto, ROS concentrations generated in the human respiratory tract in response to inhaled pollutants were estimated using a kinetic multi-layer model. These ROS values were assigned to participants’ postal codes at birth. Cox proportional hazards regression models, adjusted for confounders, were then used to estimate hazard ratios (HR) with 95% confidence intervals (CI) per unit increase in interquartile range (IQR).ResultsAfter adjusting for confounders, iron (Fe) and copper (Cu) were not significantly associated with the risk of asthma, allergic rhinitis, nor eczema. However, ROS, a measure of the combined impacts of Fe and Cu in PM2.5, was associated with an increased risk of asthma (HR = 1.11, 95% CI: 1.02–1.21, p < 0.02) per IQR. There were no statistically significant associations of ROS with allergic rhinitis (HR = 0.96, 95% CI: 0.88–1.04, p = 0.35) and eczema (HR = 1.03, 95% CI: 0.98–1.09, p = 0.24).ConclusionThese findings showed that ROS exposure in early life significantly increased the childhood risk of asthma, but not allergic rhinitis and eczema.

Targeting mucin hypersecretion in COVID-19 therapy.

Targeting mucin hypersecretion in COVID-19 therapy.

Exercise duration modulates upper and lower respiratory fluid cellularity, antiviral activity, and lung gene expression.

Exercise has substantial health benefits, but the effects of exercise on immune status and susceptibility to respiratory infections are less clear. Furthermore, there is limited research examining the effects of prolonged exercise on local respiratory immunity and antiviral activity. To assess the upper respiratory tract in response to exercise, we collected nasal lavage fluid (NALF) from human subjects (1) at rest, (2) after 45 min of moderate‐intensity exercise, and (3) after 180 min of moderate‐intensity exercise. To assess immune responses of the lower respiratory tract, we utilized a murine model to examine the effect of exercise duration on bronchoalveolar lavage (BAL) fluid immune cell content and lung gene expression. NALF cell counts did not change after 45 min of exercise, whereas 180 min significantly increased total cells and leukocytes in NALF. Importantly, fold change in NALF leukocytes correlated with the post‐exercise fatigue rating in the 180‐min exercise condition. The acellular portion of NALF contained strong antiviral activity against Influenza A in both resting and exercise paradigms. In mice undergoing moderate‐intensity exercise, BAL total cells and neutrophils decreased in response to 45 or 90 min of exercise. In lung lobes, increased expression of heat shock proteins suggested that cellular stress occurred in response to exercise. However, a broad upregulation of inflammatory genes was not observed, even at 180 min of exercise. This work demonstrates that exercise duration differentially alters the cellularity of respiratory tract fluids, antiviral activity, and gene expression. These changes in local mucosal immunity may influence resistance to respiratory viruses, including influenza or possibly other pathogens in which nasal mucosa plays a protective role, such as rhinovirus or SARS‐CoV‐2.

Influenza Virus Infection of Human Lymphocytes Occurs in the Immune Cell Cluster of the Developing Antiviral Response.

Monocytes-macrophages and lymphocytes are recruited to the respiratory tract in response to influenza virus challenge and are exposed to the virus during the establishment of immune defenses. The susceptibility of human lymphocytes to infection was assessed. The presence of monocytes-macrophages was required to attain infection of both resting and proliferating lymphocytes. Lymphocyte infection occurred in the context of immune cell clusters and was blocked by the addition of anti-intercellular adhesion molecule-1 (ICAM-1) antibody to prevent cell clustering. Both peripheral blood-derived and bronchoalveolar lymphocytes were susceptible to infection. Both CD4+ and CD8+ T lymphocytes were susceptible to influenza virus infection, and the infected CD4+ and CD8+ lymphocytes served as infectious foci for other nonpermissive or even virus-permissive cells. These data show that monocytes-macrophages and both CD4+ and CD8+ lymphocytes can become infected during the course of an immune response to influenza virus challenge. The described leukocyte interactions during infection may play an important role in the development of effective anti-influenza responses.

Mechanistic Evaluation of the Impact of Smoking and Chronic Obstructive Pulmonary Disease on the Nasal Epithelium.

Chronic obstructive pulmonary disease (COPD) is one of the major causes of chronic morbidity and mortality worldwide. The development of markers of COPD onset is hampered by the lack of accessibility to the primary target tissue, and there is a need to consider other sample sources as surrogates for biomarker research. Airborne toxicants pass through the nasal epithelium before reaching the lower airways, and the similarity with bronchial histology makes it an attractive surrogate for lower airways. In this work, we describe the transcriptomics findings from the nasal epithelia of subjects enrolled in a clinical study focusing on the identification of COPD biomarkers. Transcriptomic data were analyzed using the biological network approach that enabled us to pinpoint the biological processes affected in the upper respiratory tract in response to smoking and mild-to-moderate COPD. Our results indicated that nasal and lower airway immune responses were considerably different in COPD subjects and caution should be exercised when using upper airway samples as a surrogate for the lower airway. Nevertheless, the network approach described here could present a sensitive means of identifying smokers at risk of developing COPD.

The formation and function of tertiary lymphoid follicles in chronic pulmonary inflammation.

Tertiary lymphoid follicles (TLFs) can develop in the respiratory tract in response to infections or chronic inflammation. However, their functional relevance remains unclear because they are implicated in both protective and pathological responses. In contrast to homeostatic conditions, external antigens and damage to the lung tissue may drive TLF formation in inflamed lungs, and once established, the presence of pulmonary TLFs may signal the progression of chronic lung disease. This novel concept will be discussed in light of recent work in chronic obstructive pulmonary disease and how changes in the pulmonary microbiota may drive and direct TLF formation and function. We will also discuss the cellularity of TLFs at the pulmonary mucosa, with emphasis on the potential roles of lymphoid tissue inducer cells, and B- and T-cell aggregates, and will examine the function of key chemokines and cytokines including CXCL13 and interleukin-17, in the formation and maintenance of pulmonary TLFs.

Alterations in the proteome of the respiratory tract in response to single and multiple exposures to naphthalene.

Protein adduction is considered to be critical to the loss of cellular homeostasis associated with environmental chemicals undergoing metabolic activation. Despite considerable effort, our understanding of the key proteins mediating the pathologic consequences from protein modification by electrophiles is incomplete. This work focused on naphthalene (NA) induced acute injury of respiratory epithelial cells and tolerance which arises after multiple toxicant doses to define the initial cellular proteomic response and later protective actions related to tolerance. Airways and nasal olfactory epithelium from mice exposed to 15 ppm NA either for 4 h (acute) or for 4 h/day × 7 days (tolerant) were used for label-free protein quantitation by LC/MS/MS. Cytochrome P450 2F2 and secretoglobin 1A1 are decreased dramatically in airways of mice exposed for 4 h, a finding consistent with the fact that CYPs are localized primarily in Clara cells. A number of heat shock proteins and protein disulfide isomerases, which had previously been identified as adduct targets for reactive metabolites from several lung toxicants, were upregulated in airways but not olfactory epithelium of tolerant mice. Protein targets that are upregulated in tolerance may be key players in the pathophysiology associated with reactive metabolite protein adduction. All MS data have been deposited in the ProteomeXchange with identifier PXD000846 (http://proteomecentral.proteomexchange.org/dataset/PXD000846).

Matrix Metalloprotease 9 Mediates Neutrophil Migration into the Airways in Response to Influenza Virus-Induced Toll-Like Receptor Signaling

The early inflammatory response to influenza virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which neutrophils gain entry to the respiratory tract and their role during pathogenesis remain unclear. Here, we report that neutrophils significantly contributed to morbidity in a pathological mouse model of influenza virus infection. Using extensive immunohistochemistry, bone marrow transfers, and depletion studies, we identified neutrophils as the predominant pulmonary cellular source of the gelatinase matrix metalloprotease (MMP) 9, which is capable of digesting the extracellular matrix. Furthermore, infection of MMP9-deficient mice showed that MMP9 was functionally required for neutrophil migration and control of viral replication in the respiratory tract. Although MMP9 release was toll-like receptor (TLR) signaling-dependent, MyD88-mediated signals in non-hematopoietic cells, rather than neutrophil TLRs themselves, were important for neutrophil migration. These results were extended using multiplex analyses of inflammatory mediators to show that neutrophil chemotactic factor, CCL3, and TNFα were reduced in the Myd88 −/− airways. Furthermore, TNFα induced MMP9 secretion by neutrophils and blocking TNFα in vivo reduced neutrophil recruitment after infection. Innate recognition of influenza virus therefore provides the mechanisms to induce recruitment of neutrophils through chemokines and to enable their motility within the tissue via MMP9-mediated cleavage of the basement membrane. Our results demonstrate a previously unknown contribution of MMP9 to influenza virus pathogenesis by mediating excessive neutrophil migration into the respiratory tract in response to viral replication that could be exploited for therapeutic purposes.

Immune responsiveness to inhaled antigens: local antibody production in the respiratory tract in health and lung diseases.

The pulmonary defence mechanism in summer type hypersensitivity pneumonitis induced by Trichosporon cutaneum was investigated. We have studied the antibody response to fungal antigens in sera and bronchoalveolar lavage (BAL) fluids from patients with summer type hypersensitivity pneumonitis, bird fancier's lung, interstitial pneumonia associated with collagen vascular disease (INT-PNE), and from normal volunteers. Antigens extracted from fungi frequently isolated from home environments were used in ELISA to detect IgG and IgA antibodies in sera and BAL fluids. The results of the present study show that antibody titre in the respiratory tract to a variety of fungi from home environments is modulated by ongoing pulmonary inflammation, and that antibody production against inhaled antigens is altered by pulmonary inflammation resulting from diverse pathogenesis. This study concludes that the preexisting pulmonary inflammatory disease alters antibody production in the respiratory tract in response to inhaled fungi, and that the type of alteration depends in part on the etiology of the preexisting disease.

Risk assessment of formaldehyde for the general population in Japan

Formaldehyde is used in the production of resins, molding compounds, photographic film, bactericide, and tissue preservative. The purpose of this study was to provide an up-to-date critical review of the information to the toxicological profile of formaldehyde, and to assess the risk of formaldehyde for the general population in Japan. Inhaled formaldehyde is an effective sensory irritant at a dosage of 0.5 ppm in mice. Following inhalation in laboratory animals, more than 6 ppm formaldehyde causes degenerative non-neoplastic effects in mice and monkeys and nasal tumors in rats. It is considered that formaldehyde induces genotoxic effects directly in vitro and secondarily in vivo. Sensory irritation of the eyes and respiratory tract in response to inhalation exposure to formaldehyde has been reported at 0.08 ppm and above in human study. Formaldehyde is carcinogenic at the site of contact as a consequence of epithelial cell regenerative proliferation resulting from cytotoxicity and mutation, based on studies in both animals and humans. Levels of formaldehyde in atmosphere detected in rural, suburban, and urban areas in Japan were 2.5–3.2 ppb from 1998 to 2003. The majority of the population is exposed to atmosphere concentrations of formaldehyde less than those associated with sensory irritation. The reference concentration of formaldehyde in atmosphere for the Japanese general population is recommended to be 0.01 ppm.

Are Drosophila a Useful Model for Understanding the Toxicity of Inhaled Oxidative Pollutants: A Review

Oxidative atmospheric pollutants represent a significant stress and cause injury to both vertebrate and invertebrate species. In both, the biosurfaces of their respiratory apparatus are directly exposed to oxidizing pollutant-induced stresses. Respiratory-tract surfaces contain integrated antioxidant systems that appear to provide a primary defense against environmental insults caused by inhaled atmospheric reactive oxygen species (ROS) and reactive nitrogen species (RNS), whether gaseous or particulate. When the biosurface antioxidant defenses are overwhelmed, oxidative and nitrosative stress to the acellular and cellular components of the exposed biosurfaces can ensue via direct chemical reactions that lead to the induction of inflammatory, adaptive, injurious, and reparative processes. The study of model invertebrates (e.g., Drosophila) has a long history of yielding valuable insights into both fundamental biology and pathobiology. Mutants and/or transgenic insects, with specific alterations in key components of innate and/or adaptive antioxidant defense systems and immune genes, offer opportunities to dissect the complex systems that maintain respiratory tract surface defenses against environmental oxidants and the ensuing host responses. In this article, we use a comparative absfont approach to consider interactions of atmospheric oxidant pollutants with selected biosystems. We focused primarily on ozone (O3 ) as the pollutant, vertebrate and invertebrate respiratory tracts as the exposed biosystems, and nonenzymatic micronutrient antioxidants as significant contributors to overall antioxidant defense strategies. We present parallels among these diverse organisms with regard to their protective strategies against environmental atmospheric oxidants, with particular focus given to using the invertebrate Drosophila as a potentially useful model for vertebrate respiratory-tract responses to inhaled oxidants specifically and pollutants in general. We conclude that the insect respiratory system has considerable promise toward understanding novel aspects of vertebrate respiratory tract responses to inhaled oxidative environmental challenges.

The toxicity of H 2O 2 on the ionic homeostasis of airway epithelial cells in vitro

Oxygen species may be formed in the air spaces of the respiratory tract in response to environmental pollution such as particulate matter. The mechanisms and target molecules of these oxidants are still mainly unknown but may involve modifications of the ionic homeostasis in epithelial cells. Cytosolic concentrations of Ca 2+ (Fura2) and Na + (SBFI) and short-circuit current (Isc) were followed in primary cultures of human nasal epithelial cells and in the cell line 16HBE14o − after exposure to H 2O 2 or ·OH (H 2O 2+Fe 2+). Cells were grown on glass coverslips for ionic imaging or on permeable snapwell inserts for Isc studies. Exposure of the apical as well as the basal side of the cultures to H 2O 2 or ·OH induced a concentration-dependent transient increase in Isc which is due to a transient secretion of Cl −. Ca i also increased transiently with approximately the same kinetics. The response was dependent on the release of calcium from intracellular stores. Na i on the contrary increased steadily over more than an hour. When the apical membrane was permeabilized with gramicidin, ·OH inhibited the Na + current (a measure of Na +-K +-ATPase activity in the baso-lateral membrane). The arrest of the pump was significant after 30 min exposure to oxidant. On the other hand no increase in the apical or baso-lateral sodium conductances could be detected. The progressive arrest of the Na +/K +-pump may contribute to the sustained elevation of Na i. This strong modification in the cellular ionic homeostasis may participate in the stress response of the respiratory epithelium through alterations in signal transduction pathways.

Age and immunity to respiratory tract infections

Immunological reactions that occur in the respiratory tract in response to infectious agents have recently gained distinct attention. Humoral (1–20) and cellular immune reactions (16, 21–34) have been identified in the lungs of a number of animal species and of man. Respiratory tract infections occur frequently among the elderly and constitute one of the leading causes of death. Aged humans have a greater mortality from pneumonia (35), influenza (36), tuberculosis (37), infective endocarditis (38), urinary tract (39) and intraabdominal (40) infections. Perla and Marmorston reviewed the effects of aging on natural resistance to infection (41–42), and focused on four factors as major determinants of resistance in old age: (a) changes in structure and function of vital organs, especially endocrine glands and the splenic lymphatic apparatus; (b) underlying pathological conditions facilitating microbial invasion; (c) alterations in circulatory and nervous systems which lead to trophic changes and tissue anoxia; and (d) prolonged subclinical vitamin and mineral deficiencies. Some investigators have postulated that the predisposition of the aged to infections is not due to a declining immune response (42–43), rather than to other physiologic changes of aging. Many studies of animals and man have linked the increase of infectious disease in the aged to reduced immunological vigor (44–47), in particular, deficiency of T-cell dependent immune responses (reviewed in 48–51). These studies which focused on the circulating immune system (peripheral blood, spleen, and peripheral lymph nodes) while clearly important, have not included information on age-related changes in the mucosal immune system. Studies on mucosal immunity are obviously relevant for elucidating the mechanisms of infectious diseases in the elderly. The importance of such information is emphasized by accumulating evidence that microorganisms entering the host encounter a functionally compartmentalized and distinct lymphoid area underlying the mucosal surfaces of the lung, genital tract, and intestine. These distinct lymphoid areas are characterized by unique immune cell populations, cell trafficking and homing patterns, and immune responsiveness (reviewed in 48, 52–54).