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The respiratory system consists of an integrated network of organs and structures that primarily function for gas exchange. In mammals, oxygen and carbon dioxide are transmitted through a complex respiratory tract, consisting of the nasal passages, pharynx, larynx, and lung. Exposure to ambient air throughout the lifespan imposes vulnerability of the respiratory system to environmental challenges that can contribute toward development of disease. The importance of the respiratory system to human health is supported by statistics from the Centers for Disease Control and Prevention; in 2015, chronic lower respiratory diseases were the third leading cause of death in the United States. In light of the significant mortality associated with respiratory conditions that afflict all ages of the human population, this review will focus on basic and preclinical research conducted in nonhuman primate models of respiratory disease. In comparison with other laboratory animals, the nonhuman primate lung most closely resembles the human lung in structure, physiology, and mucosal immune mechanisms. Studies defining the influence of inhaled microbes, pollutants, or allergens on the nonhuman primate lung have provided insight on disease pathogenesis, with the potential for elucidation of molecular targets leading to new treatment modalities. Vaccine trials in nonhuman primates have been crucial for confirmation of safety and protective efficacy against infectious diseases of the lung in a laboratory animal model that recapitulates pathology observed in humans. In looking to the future, nonhuman primate models of respiratory diseases will continue to be instrumental for translating biomedical research for improvement of human health.

Studies on sulfur dioxide as an air pollutant have shown that the breathing route, either through the mouth, the nose, or both, can alter the effect of the pollutant on the lungs. There has been little research concerning the effects of inhaled ozone on lung function, in relation to the breathing route. Six young adult males were exposed on four occasions to ozone while exercising. The subjects wore a respiratory mouthpiece attached to a facemask. They did not wear noseclips during two of the exposures, allowing breathing through the mouth and/or nose, but wore noseclips during the other two exposures, forcing them to breath only through the mouth. No significant differences were found in lung function, ventilatory patterns, or subjective symptoms, according to breathing route. This study showed that the physiologic responses to ozone are not affected by the breathing route, either through the nose or mouth, during moderate and heavy continuous exercise. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abbreviation: HDM = house dust mite Indoor allergens such as house dust mite (HDM) are a contributing factor to the development of allergy and asthma in children. There is increasing [...]

Experimental nonhuman primate models of asthma exhibit multiple features that are characteristic of an eosinophilic/T helper 2 (Th2)-high asthma subtype, characterized by the increased expression of Th2 cytokines and responsive genes, in humans. Here, we determine the molecular pathways that are present in a house dust mite–induced rhesus asthma model by analyzing the genomewide lung gene expression profile of the rhesus model and comparing it with that of human Th2-high asthma. We find that a prespecified human Th2 inflammation gene set from human Th2-high asthma is also present in rhesus asthma and that the expression of the genes comprising this gene set is positively correlated in human and rhesus asthma. In addition, as in human Th2-high asthma, the Th2 gene set correlates with physiologic markers of allergic inflammation and disease in rhesus asthma. Comparison of lung gene expression profiles from human Th2-high asthma, the rhesus asthma model, and a common mouse asthma model indicates that genes associated with Th2 inflammation are shared by all three species. However, some pathophysiologic aspects of human asthma (ie, subepithelial fibrosis, angiogenesis, neural biology, and immune host defense biology) are better represented in the gene expression profile of the rhesus model than in the mouse model. Further study of the rhesus asthma model may yield novel insights into the pathogenesis of human Th2-high asthma.

To determine whether indicators of behavioral inhibition and cortisol responses to stressful situations, obtained in infancy, were associated with asthma-related measures (atopy and airway hyperresponsiveness AHR) approximately 2 years later.

Mansoor, Jim K., Brian M. Morrissey, William F. Walby, Ken Y. Yoneda, Maya Juarez, Radhika Kajekar, John W. Severinghaus, Marlowe W. Eldridge, and Edward S. Schelegle. L-Arginine supplementation enhances exhaled NO, breath condensate VEGF, and headache at 4342 m. High Alt. Med. Biol. 6:289–300, 2005.—We examined the effect of dietary supplementation with L-arginine on breath condensate VEGF, exhaled nitric oxide (NO), plasma erythropoietin, symptoms of acute mountain sickness, and respiratory related sensations at 4342 m through the course of 24 h in seven healthy male subjects. Serum L-arginine levels increased in treated subjects at time 0, 8, and 24 h compared with placebo, indicating the effectiveness of our treatment. L-arginine had no significant effect on overall Lake Louise scores compared with placebo. However, there was a significant increase in headache within the L-arginine treatment group at 12 h compared with time 0, a change not seen in the placebo condition between these two time points. There was a trend (p = 0.087) toward greater exhaled NO and significant increases in breath condensate VEGF with L-arginine treatment, but no L-arginine effect on serum EPO. These results suggest that L-arginine supplementation increases HIF-1 stabilization in the lung, possibly through a NOdependent pathway. In total, our observations indicate that L-arginine supplementation is not beneficial in the prophylactic treatment of AMS.

Increased mucus production in asthma is an important cause of airflow obstruction during severe exacerbations. To better understand the changes in airway epithelium that lead to increased mucus production, ovalbumin-sensitized and -challenged mice were used. The phenotype of the epithelium was dramatically altered, resulting in increased numbers of mucous cells, predominantly in the proximal airways. However, the total numbers of epithelial cells per unit area of basement membrane did not change. A 75% decrease in Clara cells and a 25% decrease in ciliated cells were completely compensated for by an increase in mucous cells. Consequently, by day 22, 70% of the total epithelial cell population in the proximal airways was mucous cells. Electron microscopy illustrated that Clara cells were undergoing metaplasia to mucous cells. Conversely, epithelial proliferation, detected with 5-chloro-2-deoxyuridine immunohistochemistry, was most marked in the distal airways. Using ethidium homodimer cell labeling to evaluate necrosis and terminal dUTP nick-end labeling immunohistochemistry to evaluate apoptosis, this proliferation was accompanied by negligible cell death. In conclusion, epithelial cell death did not appear to be the stimulus driving epithelial proliferation and the increase in mucous cell numbers was primarily a result of Clara cell metaplasia.

Since the original work by Hering and Breuer (1868) on slowly adapting pulmonary stretch receptors (SARs), numerous studies have demonstrated that these receptors are the lung vagal afferents responsible for eliciting the reflexes evoked by moderate lung inflation. SARs play a role in controlling breathing pattern, airway smooth muscle tone, systemic vascular resistance, and heart rate. Both anatomical and physiological studies support the contention that SARs, by their close association with airway smooth muscle, continuously sense the tension within the myoelastic components of the airways caused by lung inflation, smooth muscle contraction, and/or tethering of small intrapulmonary airways to the lung parenchyma. As a result, the receptor field location within the tracheobronchial tree of a SAR plays an important role in its discharge pattern, with variations in airway transluminal pressure and airway smooth muscle orientation being important modulating factors. The disruption of airway myoelastic components in various pulmonary diseases would be expected to alter the discharge pattern of SARs, and contribute to changes in breathing pattern and airway smooth muscle tone. Anat Rec Part A 270A:11–16, 2003. © 2003 Wiley-Liss, Inc.

Background:Extended exposure to allergen exacerbates asthma symptoms, in part via complex interactions between inflammatory cells and mediators. One consequence of these interactions is the triggering of local and central nervous system (CNS) neuronal activity that might further exacerbate the asthmalike symptoms by causing bronchoconstriction, mucous secretion, increased microvascular leak, and cough. One CNS region that might be particularly important is the caudomedial nucleus tractus solitarius (NTS). NTS neurons not only integrate primary afferent inputs from lung sensory nerve fibers but also have direct exposure to inhaled allergens and allergen-induced blood-borne inflammatory mediators via a deficient blood-brain barrier. Given the capacity of CNS neurons to undergo plasticity, allergen-induced changes in NTS neuronal properties could contribute to the exaggerated respiratory responses to extended allergen exposure. Objective:In a recently developed rhesus monkey model of allergic asthma, we tested the hypothesis that extended exposure to allergen increases the intrinsic excitability of NTS neurons. Methods:Three adult monkeys were sensitized and then repeatedly exposed to aerosols of house dust mite allergen; 4 monkeys served as controls. Whole-cell current-clamp recordings were made to measure 3 indices of excitability: resting membrane potential, input resistance, and number of action potentials evoked by current injections. Results:Extended allergen exposure depolarized the resting membrane potential by 14% and increased the number of action potentials evoked by current injections (5-fold). Conclusion:The finding that NTS neurons in a primate model of allergic asthma undergo intrinsic increases in excitability suggests that CNS mechanisms might contribute to the exaggerated symptoms in asthmatic individuals exposed to allergen. (J Allergy Clin Immunol 2001;108:557-62.)

To establish whether allergic asthma could be induced experimentally in a nonhuman primate using a common human allergen, three female rhesus monkeys (Macaca mulatta) were sensitized with house dust mite (Dermatophagoides farinae) allergen (HDMA) by subcutaneous injection, followed by four intranasal sensitizations, and exposure to allergen aerosol 3 hours per day, 3 days per week for up to 13 weeks. Before aerosol challenge, all three monkeys skin-tested positive for HDMA. During aerosol challenge with HDMA, sensitized monkeys exhibited cough and rapid shallow breathing and increased airway resistance, which was reversed by albuterol aerosol treatment. Compared to nonsensitized monkeys, there was a fourfold reduction in the dose of histamine aerosol necessary to produce a 150% increase in airway resistance in sensitized monkeys. After aerosol challenge, serum levels of histamine were elevated in sensitized monkeys. Sensitized monkeys exhibited increased levels of HDMA-specific IgE in serum, numbers of eosinophils and exfoliated cells within lavage, and elevated CD25 expression on circulating CD4+lymphocytes. Intrapulmonary bronchi of sensitized monkeys had focal mucus cell hyperplasia, interstitial infiltrates of eosinophils, and thickening of the basement membrane zone. We conclude that a model of allergic asthma can be induced in rhesus monkeys using a protocol consisting of subcutaneous injection, intranasal instillation, and aerosol challenge with HDMA.

To assess the role of lung sensory C fibers during and after inhalation of 1 part/million ozone for 8 h, we compared breathing pattern responses and epithelial injury-inflammation-repair in rats depleted of C fibers by systemic administration of capsaicin as neonates and in vehicle-treated control animals. Capsaicin-treated rats did not develop ozone-induced rapid, shallow breathing. Capsaicin-treated rats showed more severe necrosis in the nasal cavity and greater inflammation throughout the respiratory tract than did control rats exposed to ozone. Incorporation of 5-bromo-2′-deoxyuridine (a marker of DNA synthesis associated with proliferation) into terminal bronchiolar epithelial cells was not significantly affected by capsaicin treatment in rats exposed to ozone. However, when normalized to the degree of epithelial necrosis present in each rat studied, there was less 5-bromo-2′-deoxyuridine labeling in the terminal bronchioles of capsaicin-treated rats. These observations suggest that the ozone-induced release of neuropeptides does not measurably contribute to airway inflammation but may play a role in modulating basal and reparative airway epithelial cell proliferation.

SCHELEGLE, E. S. and W. C. ADAMS. Reduced exercise time in competitive simulations consequent to low level ozone exposure. Med. Sci. Sports Exerc., Vol. 18, No. 4, pp. 408–414, 1986. Ten highly trained endurance athletes were studied to determine the effects of exposure to low ozone (O3) concentrations on simulated competitive endurance performance and associated physiological and subjective symptom responses. Each subject was randomly exposed to filtered air (FA), and to 0.12, 0.18, and 0.24 ppm O3while performing a 1 h competitive simulation protocol on a bicycle ergometer. Endurance performance was evaluated by the number of subjects unable to complete rides (last 30 min at an intense work load of ∼86 VO2max)- All subjects completed the FA exposure, whereas one, five, and seven subjects did not complete the 0.12, 0.18, and 0.24 ppm O3exposures, respectively. Statistical analysis indicated a significant (P< 0.05) increase in the inability of subjects to complete the competitive simulations with increasing O3concentration, including a significant difference between the 0.24 ppm O3and FA exposure. Significant decreases (P< 0.05) were also observed following the 0.18 and 0.24 ppm O3exposures, respectively, in forced vital capacity (-7.8 and −9.9), and forced expiratory volume in 1 s (-5.8 and −10.5). No significant O3effect was observed for exercise respiratory metabolism or ventilatory pattern responses. However, the number of reported subjective symtoms increased significantly following the 0.18 and 0.24 ppm O3protocols. These data demonstrate significant decrements in simulated competitive endurance performance and in pulmonary function, with accompanying enhanced subjective symptoms, following exposure to low O3levels commonly observed in numerous metropolitan environments during the summer months.

This study was initiated to determine the effects of ozone (O3)_on sheep airway blood flow. Twenty-three nasally intubated sheep were exposed to filtered air (n = 5), 1 ppm O3(n = 4), 2 ppm O3(n = 5), 3 ppm O3(n = 5), and 4 ppm O3(n = 4) for 3 h. Bronchial artery flow (Q̇br) was measured using a chronically implanted 20 MHz pulsed Doppler flow probe.Q̇br, mean aortic pressure, cardiac output, pulmonary artery pressure, arterial blood gases, and core temperature were monitored during the period of the exposures. Exposure to 3 and 4 ppm O3resulted in a significant increase inQ̇br (103 and 204% change, respectively) without affecting any of the other cardiopulmonary parameters measured. These results indicate that O3induces a dose dependent increase inQ̇br which is the result of a vasodilation of the bronchial vasculature which is not dependent upon changes in blood gases or upstream driving pressure.

The antifibrotic potential of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) was examined in a single intratracheal bleomycin dose hamster model of pulmonary fibrosis. Bleomycin-induced fibrosis and the effectiveness of pirfenidone treatment were assessed by measuring pulmonary functions (Cqst, TLC, VC, IC, FRC, RV) and the level of hydroxyproline in whole lung homogenates. Thirty-five male golden Syrian hamsters were randomized into four experimental groups: saline instilled and fed a control diet of rat chow (SCD, n=8); saline instilled and fed the control diet containing 0.5% (w/w) pirfenidone (SPD, n=8); bleomycin instilled and fed the control diet (BCD, n= 7); and bleomycin instilled and fed the control diet containing 0.5% pirfenidone (BPD, n=10). Twenty-one days following bleomycin instillation Cqst/TLC, TLC, VC, and IC were significantly reduced and total lung hydroxyproline levels were significantly increased in the BCD and BPD groups as compared with the SCD and SPD groups, respectively. Pirfenidone ingestion significantly attenuated these bleomycin-induced pertubations in pulmonary functions and lung hydroxyproline levels (BCD versus BPD). The data obtained in this study provide evidence of the benefical effects of pirfenidone in the hamster model of bleomycin-induced pulmonary fibrosis both at the functional and biochemical level.

A critical issue has been the observation that vaccination of children with a formalin-inactivated respiratory syncytial virus (RSV) vaccine is associated with disease enhancement. We have taken advantage of bovine RSV and our experience with this disease in calves to develop a natural model that parallels human disease. Using formalin-inactivated bovine RSV vaccine calves were either sham-vaccinated/infected, vaccinated/infected, or vaccinated/sham-infected and their clinical signs, pulmonary function, and histological lung lesions quantitatively scored. Interestingly there was significantly greater disease in vaccinated/infected calves and histological lesions in calves were similar to those of affected children. Finally, we note that vaccination did not induce neutralizing antibodies, but IgG antibodies were detected by ELISA. Our model of RSV enhanced disease is important because it provides quantifiable evidence of disease severity that can be applied to evaluate the mechanisms of immunopathology and the safety of candidate RSV vaccines.

Study objective:To quantify the effects of graded upper-airwayobstruction on the delivered tidal volume and selected parameters of pulmonary mechanics during transtracheal jet ventilation (TTJV) in a dog model.

Study objective:To quantify the delivered tidal volume andother selected measurements of pulmonary mechanics in an animal model during transtracheal jet ventilation (TTJV), with comparison to positive-pressure mechanical ventilation (PPMV) and spontaneous breathing.