Respiratory Physiology & Neurobiology 209 (2015) 1–5
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Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Foreword
Molecular basis of ventilatory disorders
This Special Issue of Respiratory Physiology and Neurobiology addresses the molecular basis for a variety of respiratory disorders. Topics such as the role of signaling and neurotransmitter cascades, lung injury, biomarkers of lung disorders, oxidative stress-related damage, immunoregulation, and treatment monitoring are discussed. All these issues attract increasing attention of late and come to the fore when attempting to resolve the interaction between molecular mechanisms and cellular responses. The articles, written by international experts in the field, blend basic and clinical science, review and critically discuss the state of current knowledge, and intend to promote research into the molecular basis of respiratory disorders. Sorting out the mechanisms underlying not only monogenic disorders but also those of complex pathophysiology and multiorgan involvement would benefit patients, leading to the advancement of target-based pharmacological management of respiratory illnesses. A group of articles address the role of oxidative state in lung damage and inflammatory disorders. Oxygen is a widely used pharmacological tool. Although ample evidence has accumulated over the past decades that oxygen helps many patients with respiratory failure, it can also cause damage to the lungs, particularly during the course of the acute respiratory distress syndrome (ARDS) in which it is given at high concentrations. Porzionato et al. (2015) present an in-depth review on the mechanisms of hyperoxic lung injury, associated with increased production of reactive oxygen species (ROS). The damage concerns an array of pulmonary cells, including pulmonary endothelial and alveolar epithelial cells. The importance of activation of mitogen activated protein kinase (MAPK) signaling cascade, notably consisting of extracellular signal regulated kinase (ERK1/2), C-Jun-terminal protein kinase (JNK1/2), and p38 kinase, by ROS emanating from mitochondria is highlighted. Studies indicate that ERK activation by hyperoxia in lung cells exerts a protective effect stimulating DNA repair and antioxidant mechanisms, and prolonging cell survival. By contrast, JNK1/2 and p38 kinase act to shorten survival by hastening cell apoptosis. Cytoprotective mechanisms against hyperoxia-induced cell damage are discussed. The authors address both in vitro and in vivo studies underscoring the complexity and difficulties in the assessment of oxygen effects. Neuromolecular mechanisms underlying the development of cardiovascular sequelae of chronic intermittent hypoxia are reviewed by Kumar et al. (2015). The authors present updated knowledge on the sequential molecular stages leading to enhanced catecholamine synthesis, due to activation of tyrosine hydroxylase,
http://dx.doi.org/10.1016/j.resp.2015.03.003 1569-9048/© 2015 Published by Elsevier B.V.
and release from adrenal medulla, the key contributor to hypertension. Increased intracellular calcium and calcium related signaling, both basal and hypoxia-evoked, and pro- and antioxidant imbalance, with a strong tilt toward the former lie at the core of intermittent hypoxia-related release of catecholamines in adrenal medulla. Prooxidative state, in turn, may be facilitated by HIF1␣/HIF-2␣ dysregulation, with the HIF-1␣, a known transcriptional upregulator of prooxidant enzymes, gaining the upper hand over the opposing antioxidant action of HIF-2␣. The authors point out that HIF-1␣ may not be induced by arterial hypoxia per se, which usually does not fall below the innately low level of tissue O2 content, but rather by intermittent hypoxia-related enhancement of carotid body chemoreflex, which increases sympathetic neural activity running down to adrenal medulla. Increased sympathetic activity, interacting with muscarinic acetylcholine receptors in adrenal medulla, would mediate intermittent hypoxia-induced changes in HIF-1␣ and redox state, ultimately leading to release of catecholamines. Despite substantial progress in evidence-laden basic research concerning hypoxia-related cardiovascular morbidity, the translational gap seems to persist regarding novel therapeutic modifications. Could allopurinol, mentioned in the article, xanthine oxidase inhibitor which prevents intermittent hypoxia-induced reactive oxygen species generation in adrenal medulla and the elevation of plasma catecholamines in the rat, commonly used for decades to treat gout in humans, alleviate cardiovascular morbidity of sleep apnea-related intermittent hypoxia? What actually is the incidence of intermittent hypoxia syndrome in allopurinol-treated gout patients, who most often are of senior age and thus the syndrome would be expected to be present quite often? Why in view of the role of oxidation, commonly used antioxidants do not work well in the sleep apnea syndrome? To this end, it seems the clinical translation of intermittent hypoxia basic research remains to be unraveled. Mokra and Kosutova (2015) review the current knowledge on the acute respiratory distress syndrome (ARDS) and its milder form the acute lung injury (ALI); either may result from a variety of pathological conditions, notably lung immaturity in neonates, sepsis, pneumonia, traumas, etc. Both syndromes have similar features of various intensity, such as hypoxia, diffuse alveolar injury, lung edema, neutrophil-derived inflammation, or surfactant dysfunction. The authors emphasize the endothelial–epithelial barrier as the site most vulnerable to injury. They present an array of possible biomarkers that could help in diagnostics and in the evaluation of
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Foreword / Respiratory Physiology & Neurobiology 209 (2015) 1–5
the patient’s response to therapy. Different biomarkers are present in the plasma or bronchoalveolar lavage fluid in the exudative and proliferative phases of lung injury. The level of biomarkers may suggest injury or activation of specific types of lung cells. The receptor of advanced glycation end-products (RAGE) is proposed to mark pneumocyte type I damage. Surfactant proteins are proposed as biomarkers of pneumocytes type II, and angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are proposed as the endothelial biomarkers of antiinflammatory and proinflammatory vein, respectively. The proliferative phase of lung injury has to do with enhanced levels of epithelial and endothelial cell markers, such as vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), or N-terminal procollagen peptide-III (N-PCP-III) as the exemplars. The molecular background of lung injury is essential for designing novel targets of therapeutic interventions in acute lung injury. Nonetheless, multiplicity of biomarkers stemming from the complex and not yet full well resolved pathogenetic mechanisms as well as individual variations in lung injury and accompanying comorbidities indicate that the clinicians are a long way off from identifying a single biomarker. The assessment of a combination of biomarkers of lung injury seems a reasonable solution for the time being. Likewise, there seems to be the lack of a biomarker for pneumonia. The article by Jackowska and Wrotek (2015) is a demonstration of progress on the issue. The authors review the current knowledge on the soluble form of urokinase plasminogen activator (suPAR) as a novel biomarker in community acquired children’s pneumonia. The idea is interesting and original. There is an increasing amount of data on the usefulness of suPAR in the assessment of disease severity, prognosis, and response to therapy. The authors discuss these problems in-depth showing pros and cons, and stating that the prognostic value of suPAR measurement looks most valuable for the time being. The knowledge about suPAR is limited in clinical settings, particularly concerning the infectious disease in both pediatric and adult respiratory medicine. This knowledge should certainly be disseminated. Asthma is the archetype chronic inflammatory disease of airways, resulting in bronchial hyperresponsiveness to allergen challenges. Despite recent progress in unraveling the pathogenetic background of allergic asthma, immunotherapy still remains the treatment that can significantly modify the disease course. To this end, it is worthwhile to consider the role of regulatory T cells (Treg cells) in the pathogenesis of bronchial hyperresponsiveness. Stelmaszczyk-Emmel (2015) provides updated views on crucial aspects of Treg cells characteristics, the influence on Treg cells of allergen specific immunotherapy and other treatment modalities, and the possibility of using Treg cells in therapy. Treg cells are a relatively young area of research. There are many subsets of Treg cells, with the new types of regulatory T cells being repeatedly unraveled and the final classification of them is still in the workings. However, the largest population of regulatory T cells is thymusderived regulatory T cells. Treg cells control the immune responses by suppressing target cells directly (cell-to cell contact), by cytokine production (e.g., IL-10), and by cytolytic proteins (e.g., perforin and granzyme B), or by modulation of dendritic cells’ maturation and function. Treg cells maintain the immune tolerance to allergens and limit incorrect or excessive immune responses. By doing so, Treg cells are able to control and modify the development of allergic reactions. Deficiency of Treg cells should thus be considered in the pathogenesis of asthma and related diseases. There is accumulating evidence that allergen specific immunotherapy involves cellular and molecular events involving Treg cells. Treg cells seem a promising way for cell-based therapy, and clinical therapeutic trials of their infusion have been initiated. Neutrophils are a potent source of ROS and a regulator of inflammation. Ciepiela et al. (2015) tackle many aspects of neutrophilic
function, such as release of cytokines, oxidative burst in cases of infection or exacerbations of asthma, the presence of neutrophilic traps in fighting invading pathogens, disturbances in apoptosis, etc. Asthma is typically associated with an increased count of neutrophils in the peripheral blood and in the bronchoalveolar lavage fluid. Mediators released from neutrophils, hamper immunity and contribute to the development and progression of asthma. They also participate in airway remodeling. Tumor necrosis factor-alpha (TNF-␣) stimulates passage of eosinophils through the endothelial basement membrane and transforming growth factor beta (TGF) stimulates fibroblast proliferation in airways. Migration of cells to the asthmatic airways depends on chemoattractive signals sent out from neutrophils. An airway hampering role of neutrophils in chronic asthma contrasts with their oxidative burst, i.e., abrupt release of ROS in response to invading pathogens, which helps abrogate pathogens. However, the most intriguing role of neutrophils is the formation of neutrophilic extracellular traps (NETs), weblike structures consisting of nucleic acids and histones released after degradation of cell membranes. NETs, formed in human asthmatic airways, capture and immobilize microorganisms. The traps may also be formed by eosinophils. This is an increasingly attractive area of research of high clinical relevance in controlling the innate immune responses to bacterial invasion. Thus, the role of neutrophils is dichotomous, capturing bacteria but also damaging healthy cells by way of oxidation. Recent data indicate that pulmonary surfactant, an active phospholipoprotein complex lining the alveolar inner surface, is a regulator of airway tonus and thus may be at play in the pathophysiology of asthma or chronic obstructive pulmonary disease. Surfactant’s role seems to go far beyond the classic reduction of the surface tension of the alveolar air–liquid interface, which counteracts alveolar atelectasis. Calkovska et al. (2015) reviews the functional role of surfactant and provides evidence for its engagement in interfacial transport and defense mechanisms, antiedematous role, and most importantly surfactant’s engagement in a direct relaxing effect on bronchial smooth muscles. The evidence is based on in vitro studies of the exogenous surfactant preparations Curosurf® and Alveofact® . These clinically used preparations, although both come from natural sources, minced pig lungs and bovine lung lavage fluid, respectively, have a different composition of phospholipoproteins. The creation of different surfactant preparations stems from the futile search for an optimal preparation that would ideally emulate the effects of natural surfactant present in the alveolar space. This has been an unresolved scientific problem, hindering the commercial use of artificial surfactant preparations, and the search continues. Nonetheless, due to surfactant’s ability to control the airway wall thickness and diameter, the use of exogenous surfactant ought to be considered in common diseases with bronchial obstruction, apart from its being a regulator of surface tension in acute respiratory distress syndrome, lung injury, or immature lungs of neonates. The time seems to have come to advocate a wider clinical use of surfactant. Oxidative stress is the major culprit in tobacco users, an unabated addiction in younger age categories, like school students, with delayed detrimental health effects, like chronic obstructive pulmonary disease at later age. Iizuka et al. (2015) present their experience on how to improve the anti-tobacco campaign among Japanese school students. The authors designed a smart breathing mask that emulates the dyspneic feelings of a COPD sufferer. Controlled breathing through the mask during preventive sessions significantly decreased the number of students willing to pick up smoking. This psychological approach enhancing disillusion to smoking is valuable in view of poor effectiveness of the majority of other explanatory anti-smoking campaigns among the youths. Cigarette smoking is the major cause, albeit preventable, of heartrelated morbidity and mortality, particularly in older age groups.
Foreword / Respiratory Physiology & Neurobiology 209 (2015) 1–5
Delgado et al. (2015) attempt to get insight into a decade long story of how best to assess the predicted power of smoking in terms of the development of coronary heart disease. The authors provide convincing evidence that the level of cotinine, a major metabolite of nicotine excreted into the urine, is a reliable marker of all cause and cardiovascular mortality alone, comparable to the quantification of cigarette smoke burden in terms of pack-years. That applies to active and passive smokers. The advantage of cotinine is that it is an objective marker devoid of the subjective, known to be grossly imprecise, self-reported estimation of pack-years [number of packyears = (packs smoked per day) × (years as a smoker)]. The study is meticulous, performed on a big cohort of subjects, and ROC curves were calculated to compare different risk prediction models. The strength of the study also lies in the prospective ongoing study design encompassing over three thousand subjects. Remaining in the domain of health effects of cigarette smoke, it is worthwhile to report a review by Avezov et al. (2015) on the oxidative stress in the oral cavity. Oral cavity is a unique environment constantly exposed to internal and external hazardous compounds as almost no other part of the body. The hazards, most notably, include cigarette smoke. Reactive oxygen and nitrogen species are ubiquitous exogenous elements, which as cellular messengers, can distort cellular signaling pathways, the basis of a great deal of diseases, including neurodegenerative ones. Endogenously, these species originate mostly from mitochondrial oxygen metabolism. The review discusses at length the major elements involved in the redox imbalance in the oral cavity, such as food and drinks, dental fixtures, or cigarette smoke. The antioxidant protection by saliva also is discussed. To this end, it should be pointed out that the power of detoxifying enzymes in saliva decreases with advancing age. Therefore, oxidative injury in the oral cavity may go unabated and may cause cancerous changes. The review provides a scientific basis for the use of antioxidative drugs and strategies to restrict the potential harm being done to the oral cavity. That is a very timely piece of scientific work taking into consideration a sharp rise in the oral pathologies, notably cancer, in industrialized countries. The oral orifice is the entry way for ambient air during breathing. In this respect, an interesting study on the exposure to trafficrelated pollutants and pulmonary function is worth mentioning. Badyda et al. (2015) convincingly demonstrate, studying a cohort of close to 4000 inhabitants of a big city with congested motor vehicle traffic, that living in the vicinity of busy roads impairs respiratory function, as assessed by spirometry, which may give rise to bronchial hyperresponsiveness. The culprit is reactive oxygen and nitrogen species, and particulate matter, all of which enhances the oxidative-like state. Interestingly, physical activity apparently performed in the polluted environment enables to reduce a part of the negative health effects related to traffic emissions. A few other articles in this Special Issue are concerned with crucial aspects of lung involvement in basically non-respiratory disorders. Scleroderma is an autoimmune disease involving hardening of the skin. In its severe systemic form it also affects internal organs, the lungs being one of the frequently affected. Although scleroderma is considered a fibrosing disease, the underling vascular abnormalities gain increasing attention and research interest as the underlying mechanisms of the disease. Głodkowska-Mrówka et al. (2015) focus in their article, based on the authors’ own data, on the serum marker of angiogensis, represented by vascular endothelial growth factor – VEGF, and fibrosis, represented by pigment epithelium-derived factor – PEDF, in progressive scleroderma characterized by chronic systemic and pulmonary hypertension and lung fibrosis. VEGF and PEDF were reciprocally regulated in scleroderma patients, with the VEGF/PEDF ration being increased during the long-term follow-up of patients with progressing disease. The authors conclude that the change in the ratio is a highly specific
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and sensitive long-term prognostic index in scleroderma patients. The ratio may serve as a novel biomarker of scleroderma severity. The article sheds new light on the pathogenesis of this still pretty mysterious disease and indicates the possible way of monitoring the efficacy of treatment. The role of monoamines in breathing regulation is a perennial pathophysiologic issue full of contentiousness and uncertainties. Dopamine (DA) is a putative neurotransmitter of carotid body function, released in proportion to the intensity of the chemosensory discharge in response to hypoxia. There is a consensus that DA is inhibitory for ventilation at the carotid body level, but stimulatory at the central level; albeit the notion is not universally accepted and there also are species-related exceptions. To this end, a study by Sugita et al. (2015) that shows that ventilation is affected by dopamine D2-like receptors in the basolateral amygdala is timely and raising obvious research interest. That experimental study tackles DA release, its interaction with DA-like receptors, regulation of respiratory rate, and amygdala-driven emotional control. The study attempts to distinguish between D1/D2 and pre-/postsynatic regulatory influence of emotions on ventilation by using centrally applied pharmacological DA antagonists by way of microdialysis. The results suggest that D2 post-synaptic sites in the basolateral amygdala have to do with the upregulation of breathing rate, and specifically so, as a sequel of emotional anxiety. Disruption of brain monoamine metabolism in the neonatal period gives rise to a number of developmental disorders, including cognitive, motor, and respiratory deficiencies or dysfunctions. An array of disorders is difficult to diagnose due to the over´ et al. lapping and fleetingly changeable symptoms. Szymanska (2015) in an elaborate study presents an attempt to associate clinical phenotypes of children with neurodevelopmental disorders with dopamine and serotonin metabolites, homovanillic acid and hydroxyindoleacetic acid, respectively, measured in CSF. The authors produce an extensive description and stratification of various disorders involving the central neurotransmitter-linked metabolism leading to neonate and pediatric encephalopathies. They found a decreased level of at least one metabolite in about 50% of children. Both metabolites were decreased in progressive and extrapyramidal disorders. Interestingly, homovanillic acid, a dopamine metabolite, was distinctly lower in respiratory and hypokinetic disorders characterized by high rigidity. On the other hand, epilepsy is rarely associated with a low level of monoamines. The major conclusion, therefore, is that progressive/rigid phenotype carries a high risk of biogenic amines deficiency in the brain. The strength of the article lies in the hitherto missing clinical knowledge of how to consistently and verifiably separate or distinguish clinical phenotypes of pediatric encephalopathy. Nevertheless, the molecular basis of phenotypic variability ought to be elucidated. The regulation of ventilatory chemosensory responses at the molecular level is still a limited area of understanding. It is, therefore, welcome to come across the articles dealing with the subject. The hypercapnic ventilatory response is mostly driven by the central chemoreceptors located at the ventral medullary surface and, in addition, by less recognized and accepted CO2 sensitive neurons in the brain. Aleksandrova et al. (2015) report the involvement of the central eicosanoid pathway in the ventilatory response to hypercapnia. In detail, the study points to the role of the cyclooxygenase pathway in modulation of the ventilatory response to hypercapnia via interleukin-1 in the rat. The systemic level of this and other inflammatory cytokines has been reported to increase in many respiratory diseases such as asthma or chronic obstructive pulmonary disease. Cytokines are also produced in neurons and glial cells, where they play a role in neuroimmune interactions and neuronal communication. The study demonstrates that activation of the central cyclooxygenese pathway may dampen the ventila-
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Foreword / Respiratory Physiology & Neurobiology 209 (2015) 1–5
tory response to hypercapnia. Therefore, inflammatory conditions may hamper the CO2 chemoreflex, leading to the development of hypercapnia without a compensatory increase in ventilation. This interesting article, in a sense, points to a link between central chemoreceptors and immunogenicity. The role of proinflammatory cytokines in the chemical regulation of breathing is a heady topic of late and constitutes a cutting-edge knowledge. Recent evidence suggests that signaling molecules locally produced in the carotid body, including cytokines and angiotensin II play a major role also in the function of carotid body chemoreceptors that generate the hypoxic chemoreflex (Fung, 2015). Chemoreceptor cells express cytokine and angiotensin receptors which mediate the responses in an autocrine–paracrine manner. The findings are that these receptors and the endogenous ligands are upregulated in sustained or intermittent hypoxia. These hypoxic conditions augment the chemosensory activity and also mediate the inflammatory response of the carotid body to hypoxia. Therefore, maladaptive responses of paracrine signaling in the carotid body may factor in the pathophysiology of sleep apnea or sustained high altitude hypoxia. High altitude hypoxia may give rise to pulmonary edema, which is a non-cardiogenic pulmonary edema characterized by a constellation of symptoms such as dyspnea, tachypnea, cough, cyanosis, pulmonary crackles, and also cognitive dysfunction. The condition appears rapidly, typically during unacclimatized ascending of lowlanders within 2–4 days above 2500–3000 m. The condition is life-threatening. Therefore, the knowledge about epidemiology, pathophysiology, clinical symptoms, prevention, and treatment of high altitude pulmonary edema should be disseminated among clinicians, and among the lay public who intend to go to mountains. Korzeniewski et al. (2015a) give an excellent account of the factors characterizing high altitude pulmonary edema, underscoring, among others, the role of activation of proinflammatory cytokine signaling pathways. The authors also give valuable preventive and therapeutic tips; the former consisting mostly of acclimatization and the latter consisting of treating with a calcium channel blocker, nifidepine, and/or a long acting beta-2 agonist, sidenafil. High altitude is a harsh environmental condition that has a multiorgan impact, foremost including the way of breathing and the brain function. A kind of similar health hazards are involved with military personnel engaged in battlefield operations or training courses. These are quite often extremely harsh environmental conditions, involving not only hypoxia, but often a combination of temperature changes, pollution, airborne contaminants desert dust, and others. Here, dominant symptoms are those of respiratory tract infections, often by unknown causative pathogens. Acute respiratory distress is the principle reason for out- or inpatient treatment among military personnel, with the incidence exceeding that of the adult civilian population by up to three-fold (Korzeniewski et al., 2015b). The theme of respiratory ailments, in particular of the infectious vein, in the setting of military duties and active military operation theaters is seldom tackled, despite being of essential importance in the contemporary world. Any edition devoted to respiration can hardly avoid the subject of lung cancer, and this Special Issue is no exception to that, particularly when dealing with molecular aspects. Simasi et al. (2015) in an original research article attempt to get insight into the cause of resistance to a novel class of drugs, tyrosine kinase inhibitors, used for treatment of lung cancer. There are currently two such drugs, targeting specific intracellular molecules rather than acting across the board in the cell: erlotinib and gefitinib. Both get an increasing attention and use, due to a better profile of side effects and efficacy at least in the beginning phase of treatment. The problem lies in the resistance developing over time. The authors study the gene expression of the BCL2 family of proteins and find that
the anti-apoptotic BCL2 is increased in resistant cells and BIM-EL is, by contrast, increased in sensitive cells and decreased in resistant cells. Thus, a counter regulatory effect of the two proteins is described. Although the mechanism of drug resistance in lung cancer has not been fully resolved, the research widens our knowledge on the subject and is the source of ideas for further directions of relevant studies. The breath is a promising frontier of biomedical investigation as it is affected by metabolic processes, from physical to neural activity. Thus, exhaled breath analysis evolves into an area of practical research and use regarding the diagnosis and treatment monitoring of an array of pathological conditions; some of them not realistically thought of before in terms of exhaled breath usefulness. Mazzatenta et al. (2015a) demonstrate a distinctly different distribution profile of exhaled volatile organic compounds (VOCs) in centenarians as compared with younger seniors and young healthy subjects. The putative mechanism of the exhaled breath approach is based upon changes in the metabolites released, being a reflection of the state of the biological system investigated. This is the first ever study of exhaled VOCs across age-groups, with particular emphasis on centenarians who may be considered as a model of human longevity and the physiological process of aging. Laboratory studies have so far failed to pinpoint a biomarker of senescence. Changes in the distribution profile of VOCs compounds found in the real time analysis of exhaled breath hold promise as a substitute to such a biomarker. The study on exhaled breath content above outlined pertains to another one, recently published, which demonstrates distinct alterations in VOCs in Alzheimer’s disease (AD). The authors have provided a finger print of VOCs distribution in AD, which is appreciably different from that present in healthy subjects (Mazzatenta et al., 2015b). The findings demonstrate that exhaled VOCs may reflect the neuronal metabolism and its pathological changes in neurodegenerative diseases. Exhaled breath analysis of VOCs seems a promising early diagnostic and screening tool. Respiration is a challenging field of the scientific study. New incoming information builds up continuously on previous findings. This Special Issue is a worthwhile and timely addition to the actual state-of-the-art knowledge in the area of molecular underpinnings of ventilatory disorders. The articles concern the most common and recently widespread disorders underlain by inflammation in the respiratory tree, pathological immune responses, respiratory allergies, pneumonias, lung cancer, disordered neurotransmitter metabolism, and others. These clinical conditions are underlain by molecular dysfunction related to disordered expression and metabolism of proinflammatory cytokines, neurotransmitters, or impaired function of enzymes regulating bronchial tone and redox status, all of which underscores the value of blending basic with clinical research. There is a need to refine the understanding of molecular traits that we currently hold as having promise in the resolution of disease mechanisms or in the search for novel disease biomarkers. Conceptual approaches have to accept the complexity of interactions of bodily functions to attain the objective of early detection, evidence-based treatment, or prevention of respiratory ailments. Hopefully, this Special Issue will inspire future research ideas in the respiratory field of science.
References Aleksandrova, N.P., Danilova, G.A., Aleksandrov, V.G., 2015. Role of cyclooxygenase pathway in modulation of the ventilatory response to hypercapnia by interleukin-1 in rats. Respir. Physiol. Neurobiol. 209, 85–90. Avezov, K., Reznick, A.Z., Aizenbud, D., 2015. Oxidative stress in the oral cavity: sources and pathological outcomes. Respir. Physiol. Neurobiol. 209, 91–94. ˛ Badyda, A.J., Dabrowiecki, P., Czechowski, P.O., Majewski, G., 2015. Risk of bronchi obstruction among non-smokers: review of environmental factors affecting bronchoconstriction. Respir. Physiol. Neurobiol. 209, 39–46.
Foreword / Respiratory Physiology & Neurobiology 209 (2015) 1–5 Calkovska, A., Uhliarova, B., Joskova, M., Franova, S., Kolomaznik, M., Calkovsky, V., Smolarova, S., 2015. Pulmonary surfactant in the airway physiology: a direct relaxing effect on the smooth muscle. Respir. Physiol. Neurobiol. 209, 95–105. Ciepiela, O., Ostafina, M., Demkow, U., 2015. Neutrophils in asthma – a review. Respir. Physiol. Neurobiol. 209, 13–16. Delgado, G., Siekmeier, R., Krämer, B.K., Maerz, W., Kleber, M.E., 2015. Cotinine as a marker for risk prediction in the LUdwigshafen Risk and Cardiovascular Health Study. Respir. Physiol. Neurobiol. 209, 17–22. Fung, M.L., 2015. Expressions of angiotensin and cytokine receptors in the paracrine signaling of the carotid body in hypoxia and sleep apnea. Respir. Physiol. Neurobiol. 209, 6–12. ´ Głodkowska-Mrówka, E., Górska, E., Ciurzynski, M., Stelmaszczyk-Emmel, A., ´ A., Ciepiela, O., Pruszczyk, P., Demkow, Bienias, P., Irzyk, K., Siwicka, M., Lipinska, U., 2015. Pro- and antiangiogenic markers in patients with pulmonary complications of systemic scleroderma. Respir. Physiol. Neurobiol. 209, 69–75. Iizuka, M., Tomita, K., Takeshima, R., 2015. Experience-oriented tobacco-use prevention lecture using a COPD-simulation mask for junior high school students. Respir. Physiol. Neurobiol. 209, 28–32. Jackowska, T., Wrotek, A., 2015. The role of the soluble urokinase plasminogen activator (suPAR) in children with pneumonia. Respir. Physiol. Neurobiol. 209, 120–123. Korzeniewski, K., Nitsch-Osuch, A., Guzek, A., Juszczak, D., 2015a. High altitude pulmonary edema in mountain climbers. Respir. Physiol. Neurobiol. 209, 33–38. Korzeniewski, K., Nitsch-Osuch, A., Koniora, M., Lass, A., 2015b. Respiratory tract infections in the military environment. Respir. Physiol. Neurobiol. 209, 76–80. Kumar, G.K., Nanduri, J., Peng, Y.-J., Prabhakar, N.R., 2015. Neuromolecular mechanisms mediating the effects of chronic intermittent hypoxia on adrenal medulla. Respir. Physiol. Neurobiol. 209, 115–119.
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Mazzatenta, A., Pokorski, M., Di Giulio, C., 2015a. Real time volatile organic compounds in centenarians. Respir. Physiol. Neurobiol. 209, 47–51. Mazzatenta, A., Pokorski, M., Sartucci, F., Domenici, L., Di Giulio, C., 2015b. Volatile organic compound (VOCs) fingerprint of Alzheimer’s disease. Respir. Physiol. Neurobiol. 209, 81–84. Mokra, D., Kosutova, P., 2015. Biomarkers in acute lung injury. Respir. Physiol. Neurobiol. 209, 52–58. Porzionato, A., Sfriso, M.M., Mazzatenta, A., Macchi, V., De Caro, R., Di Giulio, C., 2015. Effects of hyperoxia exposure on signal transduction pathways in the lung. Respir. Physiol. Neurobiol. 209, 106–114. Simasi, J., Oelkrug, C., Schubert, A., Nieber, K., Gillissen, A., 2015. The role of BIMEL and BCL2-␣ on the efficacy of erlotinib and efitinib in lung cancer. Respir. Physiol. Neurobiol. 209, 64–68. Stelmaszczyk-Emmel, A., 2015. Regulatory T cells in children with allergy and asthma: it is time to act. Respir. Physiol. Neurobiol. 209, 59–63. Sugita, T., Kanamaru, M., Iizuka, M., Sato, K., Tsukada, S., Kawamura, M., Homma, I., Izumizaki, M., 2015. Breathing is affected by dopamine D2-like receptors in the basolateral amygdala. Respir. Physiol. Neurobiol. 209, 23–27. ´ Szymanska, K., Ku´smierska, K., Nowacka, M., Sykut-Cegielska, J., Demkow, U., 2015. Phenotypic features of children with neurodevelopmental diseases in relation to biogenic amines. Respir. Physiol. Neurobiol. 209, 124–132.
Mieczyslaw Pokorski Public Higher Medical Professional School in Opole and Institute of Psychology, Opole University, Opole, Poland E-mail address: m [email protected]
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Foreword
Molecular basis of ventilatory disorders
This Special Issue of Respiratory Physiology and Neurobiology addresses the molecular basis for a variety of respiratory disorders. Topics such as the role of signaling and neurotransmitter cascades, lung injury, biomarkers of lung disorders, oxidative stress-related damage, immunoregulation, and treatment monitoring are discussed. All these issues attract increasing attention of late and come to the fore when attempting to resolve the interaction between molecular mechanisms and cellular responses. The articles, written by international experts in the field, blend basic and clinical science, review and critically discuss the state of current knowledge, and intend to promote research into the molecular basis of respiratory disorders. Sorting out the mechanisms underlying not only monogenic disorders but also those of complex pathophysiology and multiorgan involvement would benefit patients, leading to the advancement of target-based pharmacological management of respiratory illnesses. A group of articles address the role of oxidative state in lung damage and inflammatory disorders. Oxygen is a widely used pharmacological tool. Although ample evidence has accumulated over the past decades that oxygen helps many patients with respiratory failure, it can also cause damage to the lungs, particularly during the course of the acute respiratory distress syndrome (ARDS) in which it is given at high concentrations. Porzionato et al. (2015) present an in-depth review on the mechanisms of hyperoxic lung injury, associated with increased production of reactive oxygen species (ROS). The damage concerns an array of pulmonary cells, including pulmonary endothelial and alveolar epithelial cells. The importance of activation of mitogen activated protein kinase (MAPK) signaling cascade, notably consisting of extracellular signal regulated kinase (ERK1/2), C-Jun-terminal protein kinase (JNK1/2), and p38 kinase, by ROS emanating from mitochondria is highlighted. Studies indicate that ERK activation by hyperoxia in lung cells exerts a protective effect stimulating DNA repair and antioxidant mechanisms, and prolonging cell survival. By contrast, JNK1/2 and p38 kinase act to shorten survival by hastening cell apoptosis. Cytoprotective mechanisms against hyperoxia-induced cell damage are discussed. The authors address both in vitro and in vivo studies underscoring the complexity and difficulties in the assessment of oxygen effects. Neuromolecular mechanisms underlying the development of cardiovascular sequelae of chronic intermittent hypoxia are reviewed by Kumar et al. (2015). The authors present updated knowledge on the sequential molecular stages leading to enhanced catecholamine synthesis, due to activation of tyrosine hydroxylase,
http://dx.doi.org/10.1016/j.resp.2015.03.003 1569-9048/© 2015 Published by Elsevier B.V.
and release from adrenal medulla, the key contributor to hypertension. Increased intracellular calcium and calcium related signaling, both basal and hypoxia-evoked, and pro- and antioxidant imbalance, with a strong tilt toward the former lie at the core of intermittent hypoxia-related release of catecholamines in adrenal medulla. Prooxidative state, in turn, may be facilitated by HIF1␣/HIF-2␣ dysregulation, with the HIF-1␣, a known transcriptional upregulator of prooxidant enzymes, gaining the upper hand over the opposing antioxidant action of HIF-2␣. The authors point out that HIF-1␣ may not be induced by arterial hypoxia per se, which usually does not fall below the innately low level of tissue O2 content, but rather by intermittent hypoxia-related enhancement of carotid body chemoreflex, which increases sympathetic neural activity running down to adrenal medulla. Increased sympathetic activity, interacting with muscarinic acetylcholine receptors in adrenal medulla, would mediate intermittent hypoxia-induced changes in HIF-1␣ and redox state, ultimately leading to release of catecholamines. Despite substantial progress in evidence-laden basic research concerning hypoxia-related cardiovascular morbidity, the translational gap seems to persist regarding novel therapeutic modifications. Could allopurinol, mentioned in the article, xanthine oxidase inhibitor which prevents intermittent hypoxia-induced reactive oxygen species generation in adrenal medulla and the elevation of plasma catecholamines in the rat, commonly used for decades to treat gout in humans, alleviate cardiovascular morbidity of sleep apnea-related intermittent hypoxia? What actually is the incidence of intermittent hypoxia syndrome in allopurinol-treated gout patients, who most often are of senior age and thus the syndrome would be expected to be present quite often? Why in view of the role of oxidation, commonly used antioxidants do not work well in the sleep apnea syndrome? To this end, it seems the clinical translation of intermittent hypoxia basic research remains to be unraveled. Mokra and Kosutova (2015) review the current knowledge on the acute respiratory distress syndrome (ARDS) and its milder form the acute lung injury (ALI); either may result from a variety of pathological conditions, notably lung immaturity in neonates, sepsis, pneumonia, traumas, etc. Both syndromes have similar features of various intensity, such as hypoxia, diffuse alveolar injury, lung edema, neutrophil-derived inflammation, or surfactant dysfunction. The authors emphasize the endothelial–epithelial barrier as the site most vulnerable to injury. They present an array of possible biomarkers that could help in diagnostics and in the evaluation of
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the patient’s response to therapy. Different biomarkers are present in the plasma or bronchoalveolar lavage fluid in the exudative and proliferative phases of lung injury. The level of biomarkers may suggest injury or activation of specific types of lung cells. The receptor of advanced glycation end-products (RAGE) is proposed to mark pneumocyte type I damage. Surfactant proteins are proposed as biomarkers of pneumocytes type II, and angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are proposed as the endothelial biomarkers of antiinflammatory and proinflammatory vein, respectively. The proliferative phase of lung injury has to do with enhanced levels of epithelial and endothelial cell markers, such as vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), or N-terminal procollagen peptide-III (N-PCP-III) as the exemplars. The molecular background of lung injury is essential for designing novel targets of therapeutic interventions in acute lung injury. Nonetheless, multiplicity of biomarkers stemming from the complex and not yet full well resolved pathogenetic mechanisms as well as individual variations in lung injury and accompanying comorbidities indicate that the clinicians are a long way off from identifying a single biomarker. The assessment of a combination of biomarkers of lung injury seems a reasonable solution for the time being. Likewise, there seems to be the lack of a biomarker for pneumonia. The article by Jackowska and Wrotek (2015) is a demonstration of progress on the issue. The authors review the current knowledge on the soluble form of urokinase plasminogen activator (suPAR) as a novel biomarker in community acquired children’s pneumonia. The idea is interesting and original. There is an increasing amount of data on the usefulness of suPAR in the assessment of disease severity, prognosis, and response to therapy. The authors discuss these problems in-depth showing pros and cons, and stating that the prognostic value of suPAR measurement looks most valuable for the time being. The knowledge about suPAR is limited in clinical settings, particularly concerning the infectious disease in both pediatric and adult respiratory medicine. This knowledge should certainly be disseminated. Asthma is the archetype chronic inflammatory disease of airways, resulting in bronchial hyperresponsiveness to allergen challenges. Despite recent progress in unraveling the pathogenetic background of allergic asthma, immunotherapy still remains the treatment that can significantly modify the disease course. To this end, it is worthwhile to consider the role of regulatory T cells (Treg cells) in the pathogenesis of bronchial hyperresponsiveness. Stelmaszczyk-Emmel (2015) provides updated views on crucial aspects of Treg cells characteristics, the influence on Treg cells of allergen specific immunotherapy and other treatment modalities, and the possibility of using Treg cells in therapy. Treg cells are a relatively young area of research. There are many subsets of Treg cells, with the new types of regulatory T cells being repeatedly unraveled and the final classification of them is still in the workings. However, the largest population of regulatory T cells is thymusderived regulatory T cells. Treg cells control the immune responses by suppressing target cells directly (cell-to cell contact), by cytokine production (e.g., IL-10), and by cytolytic proteins (e.g., perforin and granzyme B), or by modulation of dendritic cells’ maturation and function. Treg cells maintain the immune tolerance to allergens and limit incorrect or excessive immune responses. By doing so, Treg cells are able to control and modify the development of allergic reactions. Deficiency of Treg cells should thus be considered in the pathogenesis of asthma and related diseases. There is accumulating evidence that allergen specific immunotherapy involves cellular and molecular events involving Treg cells. Treg cells seem a promising way for cell-based therapy, and clinical therapeutic trials of their infusion have been initiated. Neutrophils are a potent source of ROS and a regulator of inflammation. Ciepiela et al. (2015) tackle many aspects of neutrophilic
function, such as release of cytokines, oxidative burst in cases of infection or exacerbations of asthma, the presence of neutrophilic traps in fighting invading pathogens, disturbances in apoptosis, etc. Asthma is typically associated with an increased count of neutrophils in the peripheral blood and in the bronchoalveolar lavage fluid. Mediators released from neutrophils, hamper immunity and contribute to the development and progression of asthma. They also participate in airway remodeling. Tumor necrosis factor-alpha (TNF-␣) stimulates passage of eosinophils through the endothelial basement membrane and transforming growth factor beta (TGF) stimulates fibroblast proliferation in airways. Migration of cells to the asthmatic airways depends on chemoattractive signals sent out from neutrophils. An airway hampering role of neutrophils in chronic asthma contrasts with their oxidative burst, i.e., abrupt release of ROS in response to invading pathogens, which helps abrogate pathogens. However, the most intriguing role of neutrophils is the formation of neutrophilic extracellular traps (NETs), weblike structures consisting of nucleic acids and histones released after degradation of cell membranes. NETs, formed in human asthmatic airways, capture and immobilize microorganisms. The traps may also be formed by eosinophils. This is an increasingly attractive area of research of high clinical relevance in controlling the innate immune responses to bacterial invasion. Thus, the role of neutrophils is dichotomous, capturing bacteria but also damaging healthy cells by way of oxidation. Recent data indicate that pulmonary surfactant, an active phospholipoprotein complex lining the alveolar inner surface, is a regulator of airway tonus and thus may be at play in the pathophysiology of asthma or chronic obstructive pulmonary disease. Surfactant’s role seems to go far beyond the classic reduction of the surface tension of the alveolar air–liquid interface, which counteracts alveolar atelectasis. Calkovska et al. (2015) reviews the functional role of surfactant and provides evidence for its engagement in interfacial transport and defense mechanisms, antiedematous role, and most importantly surfactant’s engagement in a direct relaxing effect on bronchial smooth muscles. The evidence is based on in vitro studies of the exogenous surfactant preparations Curosurf® and Alveofact® . These clinically used preparations, although both come from natural sources, minced pig lungs and bovine lung lavage fluid, respectively, have a different composition of phospholipoproteins. The creation of different surfactant preparations stems from the futile search for an optimal preparation that would ideally emulate the effects of natural surfactant present in the alveolar space. This has been an unresolved scientific problem, hindering the commercial use of artificial surfactant preparations, and the search continues. Nonetheless, due to surfactant’s ability to control the airway wall thickness and diameter, the use of exogenous surfactant ought to be considered in common diseases with bronchial obstruction, apart from its being a regulator of surface tension in acute respiratory distress syndrome, lung injury, or immature lungs of neonates. The time seems to have come to advocate a wider clinical use of surfactant. Oxidative stress is the major culprit in tobacco users, an unabated addiction in younger age categories, like school students, with delayed detrimental health effects, like chronic obstructive pulmonary disease at later age. Iizuka et al. (2015) present their experience on how to improve the anti-tobacco campaign among Japanese school students. The authors designed a smart breathing mask that emulates the dyspneic feelings of a COPD sufferer. Controlled breathing through the mask during preventive sessions significantly decreased the number of students willing to pick up smoking. This psychological approach enhancing disillusion to smoking is valuable in view of poor effectiveness of the majority of other explanatory anti-smoking campaigns among the youths. Cigarette smoking is the major cause, albeit preventable, of heartrelated morbidity and mortality, particularly in older age groups.
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Delgado et al. (2015) attempt to get insight into a decade long story of how best to assess the predicted power of smoking in terms of the development of coronary heart disease. The authors provide convincing evidence that the level of cotinine, a major metabolite of nicotine excreted into the urine, is a reliable marker of all cause and cardiovascular mortality alone, comparable to the quantification of cigarette smoke burden in terms of pack-years. That applies to active and passive smokers. The advantage of cotinine is that it is an objective marker devoid of the subjective, known to be grossly imprecise, self-reported estimation of pack-years [number of packyears = (packs smoked per day) × (years as a smoker)]. The study is meticulous, performed on a big cohort of subjects, and ROC curves were calculated to compare different risk prediction models. The strength of the study also lies in the prospective ongoing study design encompassing over three thousand subjects. Remaining in the domain of health effects of cigarette smoke, it is worthwhile to report a review by Avezov et al. (2015) on the oxidative stress in the oral cavity. Oral cavity is a unique environment constantly exposed to internal and external hazardous compounds as almost no other part of the body. The hazards, most notably, include cigarette smoke. Reactive oxygen and nitrogen species are ubiquitous exogenous elements, which as cellular messengers, can distort cellular signaling pathways, the basis of a great deal of diseases, including neurodegenerative ones. Endogenously, these species originate mostly from mitochondrial oxygen metabolism. The review discusses at length the major elements involved in the redox imbalance in the oral cavity, such as food and drinks, dental fixtures, or cigarette smoke. The antioxidant protection by saliva also is discussed. To this end, it should be pointed out that the power of detoxifying enzymes in saliva decreases with advancing age. Therefore, oxidative injury in the oral cavity may go unabated and may cause cancerous changes. The review provides a scientific basis for the use of antioxidative drugs and strategies to restrict the potential harm being done to the oral cavity. That is a very timely piece of scientific work taking into consideration a sharp rise in the oral pathologies, notably cancer, in industrialized countries. The oral orifice is the entry way for ambient air during breathing. In this respect, an interesting study on the exposure to trafficrelated pollutants and pulmonary function is worth mentioning. Badyda et al. (2015) convincingly demonstrate, studying a cohort of close to 4000 inhabitants of a big city with congested motor vehicle traffic, that living in the vicinity of busy roads impairs respiratory function, as assessed by spirometry, which may give rise to bronchial hyperresponsiveness. The culprit is reactive oxygen and nitrogen species, and particulate matter, all of which enhances the oxidative-like state. Interestingly, physical activity apparently performed in the polluted environment enables to reduce a part of the negative health effects related to traffic emissions. A few other articles in this Special Issue are concerned with crucial aspects of lung involvement in basically non-respiratory disorders. Scleroderma is an autoimmune disease involving hardening of the skin. In its severe systemic form it also affects internal organs, the lungs being one of the frequently affected. Although scleroderma is considered a fibrosing disease, the underling vascular abnormalities gain increasing attention and research interest as the underlying mechanisms of the disease. Głodkowska-Mrówka et al. (2015) focus in their article, based on the authors’ own data, on the serum marker of angiogensis, represented by vascular endothelial growth factor – VEGF, and fibrosis, represented by pigment epithelium-derived factor – PEDF, in progressive scleroderma characterized by chronic systemic and pulmonary hypertension and lung fibrosis. VEGF and PEDF were reciprocally regulated in scleroderma patients, with the VEGF/PEDF ration being increased during the long-term follow-up of patients with progressing disease. The authors conclude that the change in the ratio is a highly specific
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and sensitive long-term prognostic index in scleroderma patients. The ratio may serve as a novel biomarker of scleroderma severity. The article sheds new light on the pathogenesis of this still pretty mysterious disease and indicates the possible way of monitoring the efficacy of treatment. The role of monoamines in breathing regulation is a perennial pathophysiologic issue full of contentiousness and uncertainties. Dopamine (DA) is a putative neurotransmitter of carotid body function, released in proportion to the intensity of the chemosensory discharge in response to hypoxia. There is a consensus that DA is inhibitory for ventilation at the carotid body level, but stimulatory at the central level; albeit the notion is not universally accepted and there also are species-related exceptions. To this end, a study by Sugita et al. (2015) that shows that ventilation is affected by dopamine D2-like receptors in the basolateral amygdala is timely and raising obvious research interest. That experimental study tackles DA release, its interaction with DA-like receptors, regulation of respiratory rate, and amygdala-driven emotional control. The study attempts to distinguish between D1/D2 and pre-/postsynatic regulatory influence of emotions on ventilation by using centrally applied pharmacological DA antagonists by way of microdialysis. The results suggest that D2 post-synaptic sites in the basolateral amygdala have to do with the upregulation of breathing rate, and specifically so, as a sequel of emotional anxiety. Disruption of brain monoamine metabolism in the neonatal period gives rise to a number of developmental disorders, including cognitive, motor, and respiratory deficiencies or dysfunctions. An array of disorders is difficult to diagnose due to the over´ et al. lapping and fleetingly changeable symptoms. Szymanska (2015) in an elaborate study presents an attempt to associate clinical phenotypes of children with neurodevelopmental disorders with dopamine and serotonin metabolites, homovanillic acid and hydroxyindoleacetic acid, respectively, measured in CSF. The authors produce an extensive description and stratification of various disorders involving the central neurotransmitter-linked metabolism leading to neonate and pediatric encephalopathies. They found a decreased level of at least one metabolite in about 50% of children. Both metabolites were decreased in progressive and extrapyramidal disorders. Interestingly, homovanillic acid, a dopamine metabolite, was distinctly lower in respiratory and hypokinetic disorders characterized by high rigidity. On the other hand, epilepsy is rarely associated with a low level of monoamines. The major conclusion, therefore, is that progressive/rigid phenotype carries a high risk of biogenic amines deficiency in the brain. The strength of the article lies in the hitherto missing clinical knowledge of how to consistently and verifiably separate or distinguish clinical phenotypes of pediatric encephalopathy. Nevertheless, the molecular basis of phenotypic variability ought to be elucidated. The regulation of ventilatory chemosensory responses at the molecular level is still a limited area of understanding. It is, therefore, welcome to come across the articles dealing with the subject. The hypercapnic ventilatory response is mostly driven by the central chemoreceptors located at the ventral medullary surface and, in addition, by less recognized and accepted CO2 sensitive neurons in the brain. Aleksandrova et al. (2015) report the involvement of the central eicosanoid pathway in the ventilatory response to hypercapnia. In detail, the study points to the role of the cyclooxygenase pathway in modulation of the ventilatory response to hypercapnia via interleukin-1 in the rat. The systemic level of this and other inflammatory cytokines has been reported to increase in many respiratory diseases such as asthma or chronic obstructive pulmonary disease. Cytokines are also produced in neurons and glial cells, where they play a role in neuroimmune interactions and neuronal communication. The study demonstrates that activation of the central cyclooxygenese pathway may dampen the ventila-
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tory response to hypercapnia. Therefore, inflammatory conditions may hamper the CO2 chemoreflex, leading to the development of hypercapnia without a compensatory increase in ventilation. This interesting article, in a sense, points to a link between central chemoreceptors and immunogenicity. The role of proinflammatory cytokines in the chemical regulation of breathing is a heady topic of late and constitutes a cutting-edge knowledge. Recent evidence suggests that signaling molecules locally produced in the carotid body, including cytokines and angiotensin II play a major role also in the function of carotid body chemoreceptors that generate the hypoxic chemoreflex (Fung, 2015). Chemoreceptor cells express cytokine and angiotensin receptors which mediate the responses in an autocrine–paracrine manner. The findings are that these receptors and the endogenous ligands are upregulated in sustained or intermittent hypoxia. These hypoxic conditions augment the chemosensory activity and also mediate the inflammatory response of the carotid body to hypoxia. Therefore, maladaptive responses of paracrine signaling in the carotid body may factor in the pathophysiology of sleep apnea or sustained high altitude hypoxia. High altitude hypoxia may give rise to pulmonary edema, which is a non-cardiogenic pulmonary edema characterized by a constellation of symptoms such as dyspnea, tachypnea, cough, cyanosis, pulmonary crackles, and also cognitive dysfunction. The condition appears rapidly, typically during unacclimatized ascending of lowlanders within 2–4 days above 2500–3000 m. The condition is life-threatening. Therefore, the knowledge about epidemiology, pathophysiology, clinical symptoms, prevention, and treatment of high altitude pulmonary edema should be disseminated among clinicians, and among the lay public who intend to go to mountains. Korzeniewski et al. (2015a) give an excellent account of the factors characterizing high altitude pulmonary edema, underscoring, among others, the role of activation of proinflammatory cytokine signaling pathways. The authors also give valuable preventive and therapeutic tips; the former consisting mostly of acclimatization and the latter consisting of treating with a calcium channel blocker, nifidepine, and/or a long acting beta-2 agonist, sidenafil. High altitude is a harsh environmental condition that has a multiorgan impact, foremost including the way of breathing and the brain function. A kind of similar health hazards are involved with military personnel engaged in battlefield operations or training courses. These are quite often extremely harsh environmental conditions, involving not only hypoxia, but often a combination of temperature changes, pollution, airborne contaminants desert dust, and others. Here, dominant symptoms are those of respiratory tract infections, often by unknown causative pathogens. Acute respiratory distress is the principle reason for out- or inpatient treatment among military personnel, with the incidence exceeding that of the adult civilian population by up to three-fold (Korzeniewski et al., 2015b). The theme of respiratory ailments, in particular of the infectious vein, in the setting of military duties and active military operation theaters is seldom tackled, despite being of essential importance in the contemporary world. Any edition devoted to respiration can hardly avoid the subject of lung cancer, and this Special Issue is no exception to that, particularly when dealing with molecular aspects. Simasi et al. (2015) in an original research article attempt to get insight into the cause of resistance to a novel class of drugs, tyrosine kinase inhibitors, used for treatment of lung cancer. There are currently two such drugs, targeting specific intracellular molecules rather than acting across the board in the cell: erlotinib and gefitinib. Both get an increasing attention and use, due to a better profile of side effects and efficacy at least in the beginning phase of treatment. The problem lies in the resistance developing over time. The authors study the gene expression of the BCL2 family of proteins and find that
the anti-apoptotic BCL2 is increased in resistant cells and BIM-EL is, by contrast, increased in sensitive cells and decreased in resistant cells. Thus, a counter regulatory effect of the two proteins is described. Although the mechanism of drug resistance in lung cancer has not been fully resolved, the research widens our knowledge on the subject and is the source of ideas for further directions of relevant studies. The breath is a promising frontier of biomedical investigation as it is affected by metabolic processes, from physical to neural activity. Thus, exhaled breath analysis evolves into an area of practical research and use regarding the diagnosis and treatment monitoring of an array of pathological conditions; some of them not realistically thought of before in terms of exhaled breath usefulness. Mazzatenta et al. (2015a) demonstrate a distinctly different distribution profile of exhaled volatile organic compounds (VOCs) in centenarians as compared with younger seniors and young healthy subjects. The putative mechanism of the exhaled breath approach is based upon changes in the metabolites released, being a reflection of the state of the biological system investigated. This is the first ever study of exhaled VOCs across age-groups, with particular emphasis on centenarians who may be considered as a model of human longevity and the physiological process of aging. Laboratory studies have so far failed to pinpoint a biomarker of senescence. Changes in the distribution profile of VOCs compounds found in the real time analysis of exhaled breath hold promise as a substitute to such a biomarker. The study on exhaled breath content above outlined pertains to another one, recently published, which demonstrates distinct alterations in VOCs in Alzheimer’s disease (AD). The authors have provided a finger print of VOCs distribution in AD, which is appreciably different from that present in healthy subjects (Mazzatenta et al., 2015b). The findings demonstrate that exhaled VOCs may reflect the neuronal metabolism and its pathological changes in neurodegenerative diseases. Exhaled breath analysis of VOCs seems a promising early diagnostic and screening tool. Respiration is a challenging field of the scientific study. New incoming information builds up continuously on previous findings. This Special Issue is a worthwhile and timely addition to the actual state-of-the-art knowledge in the area of molecular underpinnings of ventilatory disorders. The articles concern the most common and recently widespread disorders underlain by inflammation in the respiratory tree, pathological immune responses, respiratory allergies, pneumonias, lung cancer, disordered neurotransmitter metabolism, and others. These clinical conditions are underlain by molecular dysfunction related to disordered expression and metabolism of proinflammatory cytokines, neurotransmitters, or impaired function of enzymes regulating bronchial tone and redox status, all of which underscores the value of blending basic with clinical research. There is a need to refine the understanding of molecular traits that we currently hold as having promise in the resolution of disease mechanisms or in the search for novel disease biomarkers. Conceptual approaches have to accept the complexity of interactions of bodily functions to attain the objective of early detection, evidence-based treatment, or prevention of respiratory ailments. Hopefully, this Special Issue will inspire future research ideas in the respiratory field of science.
References Aleksandrova, N.P., Danilova, G.A., Aleksandrov, V.G., 2015. Role of cyclooxygenase pathway in modulation of the ventilatory response to hypercapnia by interleukin-1 in rats. Respir. Physiol. Neurobiol. 209, 85–90. Avezov, K., Reznick, A.Z., Aizenbud, D., 2015. Oxidative stress in the oral cavity: sources and pathological outcomes. Respir. Physiol. Neurobiol. 209, 91–94. ˛ Badyda, A.J., Dabrowiecki, P., Czechowski, P.O., Majewski, G., 2015. Risk of bronchi obstruction among non-smokers: review of environmental factors affecting bronchoconstriction. Respir. Physiol. Neurobiol. 209, 39–46.
Foreword / Respiratory Physiology & Neurobiology 209 (2015) 1–5 Calkovska, A., Uhliarova, B., Joskova, M., Franova, S., Kolomaznik, M., Calkovsky, V., Smolarova, S., 2015. Pulmonary surfactant in the airway physiology: a direct relaxing effect on the smooth muscle. Respir. Physiol. Neurobiol. 209, 95–105. Ciepiela, O., Ostafina, M., Demkow, U., 2015. Neutrophils in asthma – a review. Respir. Physiol. Neurobiol. 209, 13–16. Delgado, G., Siekmeier, R., Krämer, B.K., Maerz, W., Kleber, M.E., 2015. Cotinine as a marker for risk prediction in the LUdwigshafen Risk and Cardiovascular Health Study. Respir. Physiol. Neurobiol. 209, 17–22. Fung, M.L., 2015. Expressions of angiotensin and cytokine receptors in the paracrine signaling of the carotid body in hypoxia and sleep apnea. Respir. Physiol. Neurobiol. 209, 6–12. ´ Głodkowska-Mrówka, E., Górska, E., Ciurzynski, M., Stelmaszczyk-Emmel, A., ´ A., Ciepiela, O., Pruszczyk, P., Demkow, Bienias, P., Irzyk, K., Siwicka, M., Lipinska, U., 2015. Pro- and antiangiogenic markers in patients with pulmonary complications of systemic scleroderma. Respir. Physiol. Neurobiol. 209, 69–75. Iizuka, M., Tomita, K., Takeshima, R., 2015. Experience-oriented tobacco-use prevention lecture using a COPD-simulation mask for junior high school students. Respir. Physiol. Neurobiol. 209, 28–32. Jackowska, T., Wrotek, A., 2015. The role of the soluble urokinase plasminogen activator (suPAR) in children with pneumonia. Respir. Physiol. Neurobiol. 209, 120–123. Korzeniewski, K., Nitsch-Osuch, A., Guzek, A., Juszczak, D., 2015a. High altitude pulmonary edema in mountain climbers. Respir. Physiol. Neurobiol. 209, 33–38. Korzeniewski, K., Nitsch-Osuch, A., Koniora, M., Lass, A., 2015b. Respiratory tract infections in the military environment. Respir. Physiol. Neurobiol. 209, 76–80. Kumar, G.K., Nanduri, J., Peng, Y.-J., Prabhakar, N.R., 2015. Neuromolecular mechanisms mediating the effects of chronic intermittent hypoxia on adrenal medulla. Respir. Physiol. Neurobiol. 209, 115–119.
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Mazzatenta, A., Pokorski, M., Di Giulio, C., 2015a. Real time volatile organic compounds in centenarians. Respir. Physiol. Neurobiol. 209, 47–51. Mazzatenta, A., Pokorski, M., Sartucci, F., Domenici, L., Di Giulio, C., 2015b. Volatile organic compound (VOCs) fingerprint of Alzheimer’s disease. Respir. Physiol. Neurobiol. 209, 81–84. Mokra, D., Kosutova, P., 2015. Biomarkers in acute lung injury. Respir. Physiol. Neurobiol. 209, 52–58. Porzionato, A., Sfriso, M.M., Mazzatenta, A., Macchi, V., De Caro, R., Di Giulio, C., 2015. Effects of hyperoxia exposure on signal transduction pathways in the lung. Respir. Physiol. Neurobiol. 209, 106–114. Simasi, J., Oelkrug, C., Schubert, A., Nieber, K., Gillissen, A., 2015. The role of BIMEL and BCL2-␣ on the efficacy of erlotinib and efitinib in lung cancer. Respir. Physiol. Neurobiol. 209, 64–68. Stelmaszczyk-Emmel, A., 2015. Regulatory T cells in children with allergy and asthma: it is time to act. Respir. Physiol. Neurobiol. 209, 59–63. Sugita, T., Kanamaru, M., Iizuka, M., Sato, K., Tsukada, S., Kawamura, M., Homma, I., Izumizaki, M., 2015. Breathing is affected by dopamine D2-like receptors in the basolateral amygdala. Respir. Physiol. Neurobiol. 209, 23–27. ´ Szymanska, K., Ku´smierska, K., Nowacka, M., Sykut-Cegielska, J., Demkow, U., 2015. Phenotypic features of children with neurodevelopmental diseases in relation to biogenic amines. Respir. Physiol. Neurobiol. 209, 124–132.
Mieczyslaw Pokorski Public Higher Medical Professional School in Opole and Institute of Psychology, Opole University, Opole, Poland E-mail address: m [email protected]
