Quantifying hyperoxia-mediated damage to mammalian respiratory cilia-driven fluid flow using particle tracking velocimetry optical coherence tomography.

Oxygen supplementation [hyperoxia, increased fraction of inspired oxygen (FiO 2 )] is an indispensable treatment in the intensive care unit for patients in respiratory failure. Like other treatments or drugs, hyperoxia has a risk-benefit profile that guides its clinical use. While hyperoxia is known to damage respiratory epithelium, it is unknown if damage can result in impaired capacity to generate cilia-driven fluid flow. Here, we demonstrate that quantifying cilia-driven fluid flow velocities in the sub-100 µm/s regime (sub-0.25 in./min regime) reveals hyperoxia-mediated damage to the capacity of ciliated respiratory mucosa to generate directional flow. Flow quantification was performed using particle tracking velocimetry optical coherence tomography (PTV-OCT) in ex vivo mouse trachea. The ability of PTV-OCT to detect biomedically relevant flow perturbations in the sub-100 µm/s regime was validated by quantifying temperature- and drug-mediated modulation of flow performance in ex vivo mouse trachea. Overall, PTV-OCT imaging of cilia-driven fluid flow in ex vivo mouse trachea is a powerful and straightforward approach for studying factors that modulate and damage mammalian respiratory ciliary physiology.

Novel therapeutic strategies for fibrotic lung disease: a review with a focus on epithelial-mesenchymal transition.

Airway and pulmonary fibrosis is a pathological condition associated with chronic airway inflammation. Fibrosis and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The traditional paradigm of fibrogenesis is based on the activation of local stromal cells including fibroblasts and their conversion into myofibroblasts. However, it has become apparent that several airway structural cells, including epithelial cells, endothelial cells, and pericytes, contribute to lung fibrosis through a process of molecular reprogramming. Recent studies have shown the important role of epithelial-mesenchymal transition (EMT) in airway diseases and animal models of fibrosis, suggesting that targeting EMT may be a promising strategy against fibrotic lung disease. In this article, we review the latest advances on the evidence for EMT in airway diseases, and discuss the underlying mechanisms of EMT and the roles of inflammatory mediators. We also describe recent patents that could develop into novel therapeutics.

Dietary and supplemental antioxidant and anti-inflammatory nutrient intakes and pulmonary function.

OBJECTIVE: A limited but growing body of evidence supports a significant role of antioxidant and anti-inflammatory micronutrients in pulmonary health. We investigated the associations of dietary and supplemental intakes of vitamins A, C, E and D, Se and n-3 PUFA with pulmonary function in a population-based study. DESIGN: Population-based, cross-sectional study and data analysis of fruits and vegetables, dairy products and fish, vitamins A, C, E and D, Se and n-3 PUFA supplemental intakes, pulmonary risk factors and spirometry. SUBJECTS: Chinese older adults (n 2478) aged 55 years and above in the Singapore Longitudinal Ageing Studies. RESULTS: In multiple regression models that controlled simultaneously for gender, age, height, smoking, occupational exposure and history of asthma/chronic obstructive pulmonary disease, BMI, physical activity, and in the presence of other nutrient variables, daily supplementary vitamins A/C/E (b = 0·044, SE = 0·022, P = 0·04), dietary fish intake at least thrice weekly (b = 0·058, SE = 0·016, P < 0·0001) and daily supplementary n-3 PUFA (b = 0·068, SE = 0·032, P = 0·034) were individually associated with forced expiratory volume in the first second. Supplemental n-3 PUFA was also positively associated with forced vital capacity (b = 0·091, SE = 0·045, P = 0·045). No significant association with daily dairy product intake, vitamin D or Se supplements was observed. CONCLUSIONS: The findings support the roles of antioxidant vitamins and n-3 PUFA in the pulmonary health of older persons.

[A new approach to the treatment of patients presenting with bronchial asthma and concomitant allergic rhinitis].

The present study included 73 patients presenting with bronchial asthma (BA) and concomitant allergic rhinitis (AR). Based on the results of their examination, a program of their two-step treatment was proposed including elimination therapy during 5-7 days followed by the combined treatment with the use of physical factors, such as peloid therapy, supratonal frequency currents, inhalations, massage, and remedial gymnastics. This approach allows to significantly reduce the frequency of clinical manifestations of the primary and concomitant diseases. Specifically, the incidence of daytime choking fits decreased by 66.7%, coughing by 76.7%, nasal stiffness by 60%, and rhinorrhea by 62,6 with the simultaneous acceleration of the overall clinical effect by 3-4 days. The requirement for short-acting broncholytic agents decreased after the treatment by 56.7%. Its anti-inflammatory effect in the upper and lower respiratory tract was confirmed by the results of endoscopic examination of the nasal cavity (the occurrence of mucosal hyperemia and mucosal oedema decreased by 70% and 60% respectively whereas the presence of secretion in the nasal passages was recorded 76.7% less frequently than prior to the treatment). Cytological studies of surface epithelium revealed reduced neutrophilia and eosinophilia, decreased number of goblet cells in nasal mucosa, and lowered content of sialic acids, IL-1, and IL-6 in nasal lavage. Combined therapy improved the patency of both upper and lower respiratory tract. Moreover, the number of patients with the totally controlled clinical course of BA increased by 66.6%. It was shown that remission of BA and AR persisted within 10 and 8.2 months after the treatment respectively.

Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.

Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis.

Vicks VapoRub induces mucin secretion, decreases ciliary beat frequency, and increases tracheal mucus transport in the ferret trachea.

BACKGROUND: Vicks VapoRub (VVR) [Proctor and Gamble; Cincinnati, OH] is often used to relieve symptoms of chest congestion. We cared for a toddler in whom severe respiratory distress developed after VVR was applied directly under her nose. We hypothesized that VVR induced inflammation and adversely affected mucociliary function, and tested this hypothesis in an animal model of airway inflammation. METHODS: [1] Trachea specimens excised from 15 healthy ferrets were incubated in culture plates lined with 200 mg of VVR, and the mucin secretion was compared to those from controls without VVR. Tracheal mucociliary transport velocity (MCTV) was measured by timing the movement of 4 microL of mucus across the trachea. Ciliary beat frequency (CBF) was measured using video microscopy. [2] Anesthetized and intubated ferrets inhaled a placebo or VVR that was placed at the proximal end of the endotracheal tube. We evaluated both healthy ferrets and animals in which we first induced tracheal inflammation with bacterial endotoxin (a lipopolysaccharide [LPS]). Mucin secretion was measured using an enzyme-linked lectin assay, and lung water was measured by wet/dry weight ratios. RESULTS: [1] Mucin secretion was increased by 63% over the controls in the VVR in vitro group (p < 0.01). CBF was decreased by 35% (p < 0.05) in the VVR group. [2] Neither LPS nor VVR increased lung water, but LPS decreased MCTV in both normal airways (31%) and VVR-exposed airways (30%; p = 0.03), and VVR increased MCTV by 34% in LPS-inflamed airways (p = 0.002). CONCLUSIONS: VVR stimulates mucin secretion and MCTV in the LPS-inflamed ferret airway. This set of findings is similar to the acute inflammatory stimulation observed with exposure to irritants, and may lead to mucus obstruction of small airways and increased nasal resistance.

Effect of needle puncture and electro-acupuncture on mucociliary clearance in anesthetized quails.

BACKGROUND: Acupuncture therapy for obstructive respiratory diseases has been effectively used in clinical practice and the acupuncture points or acupoints of Zhongfu and Tiantu are commonly-used acupoints to treat patients with the diseases. Since the impaired mucociliary clearance is among the most important features of airway inflammation in most obstructive respiratory diseases, the effect of needle puncture and electro-acupuncture at the specific acupoints on tracheal mucociliary clearance was investigated in anesthetized quails. METHODS: Mucociliary transport velocity on tracheal mucosa was measured through observing the optimal pathway, and fucose and protein contents in tracheal lavages were determined with biochemical methods. In the therapeutic group, needle puncture or electro-acupuncture stimulation to the acupoints was applied without or with constant current output in 2 mA and at frequency of 100 Hz for 60 minutes. In the sham group, electro-acupuncture stimulation to Liangmen was applied. RESULTS: Our present experiments demonstrated that the electro-acupuncture stimulation to Zhongfu and Tiantu significantly increased tracheal mucociliary transport velocity and decreased the content of protein in the tracheal lavage, compared with the control group. Moreover, either needle puncture or electro-acupuncture stimulation to Zhongfu and Tiantu significantly reverted the human neutrophil elastase-induced decrease in tracheal mucociliary transport velocity and human neutrophil elastase -induced increase in the contents of fucose and protein in the tracheal lavage, compared with the control group. CONCLUSION: These results suggest that either needle puncture or electro-acupuncture stimulation to the effective acupoints significantly improves both airway mucociliary clearance and the airway surface liquid and that the improvements maybe ascribed to both the special function of the points and the substantial stimulation of electricity.

Zinc metabolism in airway epithelium and airway inflammation: basic mechanisms and clinical targets. A review.

In addition to basic housekeeping roles in metalloenzymes and transcription factors, dietary zinc (Zn) is an important immunoregulatory agent, growth cofactor, and cytoprotectant with anti-oxidant, anti-apoptotic, and anti-inflammatory roles. These properties of Zn are of particular importance in maintaining homeostasis of epithelial tissues which are at the front line of defense. This review is about the role of Zn in airway epithelium (AE). The first part focuses on the cellular biology of Zn, and what is known about its distribution and function in AE. The second part of the review considers evidence for altered Zn metabolism in asthma and other chronic diseases of airway inflammation. Important issues arise from a potential therapeutic perspective as to the optimal ways to monitor circulating and epithelial Zn levels in patients and the most effective means of supplementing these levels.

Hyperresponsiveness to tobacco dust extract in sensitized guinea pig trachea.

The role of pre-existing airway inflammation in the pathogenesis of occupational airway disease is poorly understood. Previously we studied an extract of tobacco dust (TDE) and determined that it causes concentration dependent contractions of nonsensitized guinea pig trachea (GPT). In the present study animals were sensitized using Ovalbumin (OA) and subsequently challenged with an aerosol of 2.5% OA on day 21. A control group of nonsensitized GPs were divided into rings in which the epithelium was retained (EPI+) or removed (EPI-). Concentration related contractions of sensitized and nonsensitized GPTs were elicited with TDE. Sensitized GPTs demonstrated a greater contractile response to TDE than did nonsensitized GPTs. In nonsensitized animals the EPI- GPTs demonstrated a lesser response to TDE than did the EPI+. Similar findings were demonstrated in sensitized GPTs with and without epithelium. When epithelium was removed, sensitized and nonsensitized GPTs behaved similarly. Moreover, sensitized GPTs without epithelium and nonsensitized with epithelium responded similarly. These findings suggest that presensitization with an unrelated antigen enhances the response to an occupational agent and that in sensitized animals at least part of the enhanced response is mediated by the epithelial layer.

Investigation of pulmonary epithelial permeability in patients after hyperbaric oxygen therapy by 99mTc diethylenetriaminepentaacetic acid aerosol inhalation lung scintigraphy.

The aim of this study was to evaluate the possibility of pulmonary epithelial permeability damage in patients after hyperbaric oxygen therapy (HBOT) by 99mTc diethylenetriaminepentaacetic acid (99mTc-DTPA) aerosol inhalation lung scintigraphy. Twenty-five controls and 21 patients with normal chest X-rays and no cigarette smoking for at least 1 year were recruited for the study. 99mTc-DTPA aerosol inhalation lung scans were performed after 20 HBOT sessions in 21 patients with refractory osteomyelitis or diabetic foot. The HBOT with 100% oxygen at 2.5 atm absolute for 100 min was performed five times a week. Clearance rates (%/min) of 99mTc-DTPA aerosol in each lung field were calculated from the dynamic images for 30 min. Clearance rates of 99mTc-DTPA aerosol were compared between patients and controls by the unpaired t test. Thirteen patients who had 99mTc-DTPA aerosol lung scans before and after HBOT therapy studies were tested for statistical significance by using the paired t test. There was no statistically significant difference (P>0.05, unpaired t test) between patients and controls in every lung field. For the 13 patients who had 99mTc-DTPA aerosol studies both before and after 20 HBOT sessions, the results also showed no statistically significant difference (P>0.05, paired t test). It is concluded that there was no demonstrable pulmonary epithelial permeability change under current clinical HBOT protocol.