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 from 05.06.2019. (All rights reserved)

Reactive oxygen species against mysterious air ions: a hypothesis.

 

  1. N.I. Goldstein* and R. N. Goldstein

 

Keywords: air ions, reactive oxygen species, gas phase superoxide ion, H2O2 sensing, airways sensory structures

ABSTRACT

Despite decades of thorough biomedical research, to this day there is no clear understanding of the physicochemical nature of gaseous air ions and the mechanisms of their action on mammals and humans. Interpretation of air ions biological properties and effects, based on the past century views, was unproductive. The electrical nature of air ions has transformed the idea of charge, which plays an exclusively role in the properties of these particles, into the dogma of modern biology.

In this article we will present a new hypothesis of the biological activity of air ions. The concept is based on the modern understanding of the physical and chemical nature of the oxygen ion O2●– as a gas-phase superoxide O2. Experimental confirmation of this idea allowed us to consistently explain the activity of negative gas ions by the action of micromolar amounts of H2O2 (μMH2O2) as a product of dismutation of O2●–  superoxide. Taken together, both of these products are exogenous reactive oxygen species (exoROS).

From this point of view, we substantiate the concept of receptors from the respiratory tract, lungs and blood vessels as sensors for micro amounts of inhaled μMH2O2 and PAI. This discovery makes it possible to revise views on the nature and role of negative (NAI) and positive (PAI) air ions.

The new perspective allows us to better understand and more effectively use the properties of NAI as an important factor in the macro and microenvironment. The described ideas about the mechanisms of the physiological action of NAI and PAI explain well-known and reveal new therapeutic possibilities for the use of natural and artificial NAI. Examples of possible new uses of micromolar concentrations of exoROS in medicine and biotechnology are given.

ABBREVIATIONS: AI – air or atmospheric ions; NAI and PAI – negative and positive air ions; SOD – superoxide dismutase; ROS – reactive oxygen species; exoROS-exogene reactive oxygen species; GS – gas phase superoxide ion; μMH2O2 – micromolar H2O2; NEEC – single neuroepithelial endocrine cells; PNEC – neuroendocrine lung cells; NEB – neuroepithelial lung bodies (clusters); CB – carotid bodies; VNO – vomeronasal organ.

Footnotе: The nasal administration of µMH2O2 and GS, described in this article below, has nothing to do with the concentrations and methods of enteral and / or injection administration of hydrogen peroxide advertised for therapeutic purposes [22,23].

 

INTRODUCTION

Discovered almost 120 years ago, air ions have been for a long time an attractive subject of research in biology and medicine. In recent decades, however, there has been a decreased interest in AI as a biologically and environmentally important air factor. The main reasons for this are the ambiguity of the effects and the lack of a modern concept of about nature and physico-chemical mechanisms of the biological activity of negative air ions. While the literature of the last century emphasizes the key role of charge in the beneficial effects of negative air ions, these statements have never had a reliable theoretical and experimental basis. Primarily this refers to the understanding of the oxygen ion O2●–  as a key component of the negative air ions [1,2,3].

In biology, the contradiction between the beneficial effects of the atmospheric O2●–  ion and the declared danger of the „metabolic“ O2●–  radicals has remained unattended for a long time. For many decades, the O2●–  air ion was considered exclusively as a carrier of the negative charge [1,2,3,4,5,6,7,25]. At the same time, studies concerning the superoxide radical O2●–  in the condensed aqueous phase of the cells and tissues showed mainly toxic effects [8,9]. This applies not only to the superoxide radical O2●– , but also to the products of its transformation: hydrogen peroxide H2O2 and hydroxyl radical ●OH [9,10]. The dispute continues to this day, although from a chemical point of view, the symbols O2●–  and O2●–  reflects two essences of the negative oxygen ion as both ions and radical [11,12,13,14,14,15,17,31,41]. Taken together, important aspects and mechanisms of biological activity of both airborne ions that is, NAI and PAI did not receive a rational explanation.

The assumptions, experimental observations and discussions [15,16,17,31] that we published more than 30 years ago may, in our opinion, are sufficient to draw attention to our messages and subsequent papers. This did not happen. Like E. Stahl, R. Lindley, and R. Blanden, we now ask, „If this idea is so obvious to us, why does it not spread like fire?“ [18]. Why, for example, new views on the unproven role of the electric charge of negative air ions did not find the corresponding resonance in the scientific community.

Here we present the current version of our views to draw attention to air ions as components of the environment. This may contribute to the present understanding of the major aspects and mechanisms of biological activity of NAI and PAI hat have not yet been rationally explained. In this article, we will use the designations “gas-phase superoxide” (GS or O2●– ) and “micromolar H2O2” (μMH2O2) that are suitable for this paper. We use the former for O2●- radical formed in the air or in artificial gaseous medium [16,17]. The latter reflects ultra-low concentrations of hydrogen peroxide as a product of the dismutation, an inhaled GS in the respiratory tract.

AIR IONS, SUPEROXIDE AND HYDROGEN PEROXIDE

To this date, the first and most important question has remained about the physical and chemical nature of the active constituents of the NAI pool. The main interest is the oxygen ion O2●– . It is known that the electrical charges of the „small“ NAI, including the over mentioned ion, prevent its entry into the organism. This was reported in the papers [15,16,17,31,41]. This is also indicated, for example, by paper [24]. However, for decades, the most publications have been based openly or “by default” on early assumptions [4,5,25] about the invasion of the NAI and / or their electrical charges into the lungs and blood. Objective evidence of these views is missing until today.

Gas phase ion (O2●– ) shows chemical properties of the metabolic superoxide radical O2●– 

Since the mid-seventies of the last century we have been developing the concept concerning nature of biological activity of NAI [11]. We were the first to prove experimentally that the air O2●–  ion in the NAI pool is the only oxygen-containing air ion that has two physico-chemical properties – electrical and radical [15,16,17]. In our studies, we could see a higher biological activity of the pure oxygen ionization products. This was previously noted in the work [19].

Thus, the air ion O2●–  is understood today as the superoxide anion-radical O2●–  (ibid.). Our conclusion about the free radical nature of the air ion O2●–  was mentioned later in the various papers [26,27,28,29]. The fundamental importance of understanding the O2●–  air ion as the free radical is that the electrical charge of all NAIs is neutralized by contact with the body, preventing their penetration into the lungs, other organs and tissues. This question is more closely examined in the papers [16,17,24].

The gas-phase superoxide O2●– , as well as the „metabolic“ superoxide radical, can spontaneously dismute to form micromolar concentrations of hydrogen peroxide (µMH2O2). This ability of GS to form spontaneously μMH2O2 in the air and in the airway radically distinguishes it from all other NAIs. This process takes place spontaneously in the atmospheric air [30]. Much more effective dismutation of superoxide can occur with the participation of SOD on the apical surfaces of the cells of the respiratory mucosa [85]. The modulation of the effects (O2–  / O2●– ) and μMH2O2 by the enzymes SOD and catalase in vivo, in vitro and in situ is important evidence regarding the role of oxygen free radicals O2●–  in the action of the NAI. The publications [16,17] contain various experimental data confirming the radical nature of GS and the product of its transformations μMH2O2 as exoROS and the main active components of the NAI pool.

Hydrogen peroxide μMH2O2 as a product of superoxide (O2●– ) dismutation has both the physiological and therapeutic effects of NAI

Nearly half a century of experience in our studies on GS and μMH2O2 has shown that these exoROS qualitatively and to a much greater extent quantitatively reproduce all known physiological and therapeutic effects of NAI [17]. In the clinic, this is most clearly demonstrated by evidence of pain suppression in animal experiments and probands [32,33,34]. Another convincing example is the greater efficiency of GS compared to NAI in the treatment of bronchial asthma [35,36,37,38,39,40,41]. The higher physiological activity of exoROS compared to NAI may provide an explanation for the specific local and central effects of μMH2O2. At the local level, μMH2O2 contributes to the formation of adaptive effects in the tissues of the lungs. At the core of the central effects of exoROS, induction of cortisol as an endogenous anti-inflammatory hormone may play a significant role (ibid.).

Which receptor structures in the body can be influenced by inhaled NAI and PAI?

It is known that the half-life of H2O2 in lymphocytes is a thousand times longer than that of superoxide O2●– , respectively, 1ms and 1μs [42]. In the pure air, an even higher H2O2 stability can be expected. The more stable μMH2O2 can penetrate the lungs and blood without significant restrictions. As an indirect evidence of an increase in the level of H2O2 in the blood after inhalation of NAI may be a detectable increase in blood of the catalase index [4]. This observation was made in the middle of the last century, but, unfortunately, did not receive further development.

a/ Nasal mucosa and vomeronasal organ (VNO)

In humans and most Mammalia, the VNO is located in the nasal mucosa symmetrically on both sides of the nasal septum. The main known VNO functions in animals are the perception of volatile chemosignals from pheromones that regulate neuroendocrine and behavioural responses, as well as sexual and maternal behaviour [43,44,74]. As an anatomical structure, the VNO is represented in humans by a small paired recess (vomeronasal fossa) and, in contrast to animals, is not enclosed in a tubular sheath (vomer) [45-47]. According to new data, the VNO in humans persists throughout life [ibid.]. In humans and animals, the VNO via the additional olfactory pathway communicates with the medial zones of the hypothalamus and the amygdala.

We have repeatedly discussed the putative signalling function of VNO receptors upon exposure to NAI [17,31,32,33,34,35,48,53]. This assumption was justified by the position of the VNO at the inlet (first line) of the respiratory air flow and known data on the extremely short lifetime of gas ions O2●–  in the air (see above). The comparison of the GS effects with NAI deprivation in animals confirmed the important role of gas phase superoxide ions in regulating the activity of the hypothalamic-pituitary complex [48]. An indirect indication of the role of GS can be a message about the possible role of VNO neurons and neurosensory epithelium in the development of various neurodegenerative diseases of the CNS, namely of Parkinson’s disease [50]. We were able to confirm this in relation to Parkinson’s disease and forms of Parkinsonism. The clinical efficiency of exoROS in the treatment of Parkinson’s disease was indeed found in patients after therapeutic use of the μMH2O2 drug spray [51,52,53,54].

b/ Solitary neuroepithelial endocrine (NEE) cells in the epithelium of the upper respiratory tract and bronchi.

In the context of the sensitivity toward exogenous GS or µMH2O2, epithelial receptors of the larynx, trachea and bronchi are of great interest. The diffuse located neuroepithelial endocrine cells in the epithelium of these areas reach the bronchio-alveolar junction and contain serotonin (5-HT), peptide hormones and other various neural and neuroendocrine markers. The main functions of these cells are considered to be respiratory control [56,60,61,62,63,75]. Therefore, solitary cells can locally affect adjacent cells and / or smooth muscle fibers of the bronchi. The other functions of these cells have not been studied in more detail. It is believed that the main ligand of the NEE cell receptors may be H2O2 [61,62,63].

c/ Neuroendocrine solitary cells (PNEC) and neuroepithelial bodies (NEB) of the lungs.

The PNEC system in the lungs includes single cells and their innervated NEB bodies [57,58,59,63,64]. In terms of the expression of an amine, peptide, and neuroendocrine marker, single PNEC and PNEB show an identical phenotype and apparently only NEBs of the pulmonary airways are innervated (ibid.). It is assumed that the input and modulation of NEB signals is mediated through the central nervous system [59,61]. Other functions of single PNEC and NEBs in the lungs are not discussed in the available literature.

The O2-sensitive current signal of K+-channels can be modulated by H2O2 as a product of the NADPH-oxidase reaction [55,71]. In the context of the above, this may indicate on the role of exogenous µMH2O2 as a putative ligand of the K+-channels. This suggests that exogenous μMH2O2 can, along with the pO2 signal, affect the tone of the respiratory tract, pulmonary circulation and / or control of respiration. Thus, the effects of released relaxing and contractile factors in the bronchi may reflect not only changes in the concentration of O2 and NADPH oxidation-dependent formation of endogenous H2O2, but also the effect of exoROS on the modulation of homeostatic processes in the lungs.

Therefore, we postulate that the GS of inhaled air can serve as a natural source of H2O2 an exogenous regulatory factor. It was previously shown that the total deprivation of exoROS is fatal to deprived animals. Under the conditions of the maximum possible removal of NAI from the air, deep pathological changes were observed leading to the death of animals. Under these conditions, mortality reached 100% with an average life expectancy in mice of 16.2 ± 0.9 days and in rats 23.0 ± 1.1 days [17,48]. In the same time, the limited subchronic AI deprivation causes less dramatic effects on animals. In guinea pigs, limited deprivation of NAI leads to a decrease in the phagocytic activity of leukocytes, destabilization of platelets, and dysregulation of blood viscosity during an inflammatory reaction [67].

A decrease in the level of natural exoROS in polluted air can be the cause of compensatory hyperventilation of the lungs and an [O2] increase in the tissues. This can stimulate the formation of endogenous ROS and accelerate aging of the body. On the other hand, a controlled increase in the levels of inhaled GS or μMH2O2 in the inhaled air (for example, for therapeutic purposes) may serve as a signal to reduce pulmonary ventilation. This in turn reduces the level of endogenous ROS, as well as the danger of free radical pathology and the rate of aging. In addition, should also be noted that endogenous H2O2 is a product of the MAO-dependent metabolism of 5-HT in the lungs and dopamine in the carotid blood vessels. At low concentrations, the metabolic H2O2 can have a local dilatation effect on smooth muscles.

Inhalable exogenous μMH2O2 as a signalling molecule and a genetically relevant factor

It seems that the wise Nature has not limited itself to a quantitative assessment of inhaled oxygen and PO2 in the lungs and has also included an assessment of the quality of inhaled air in the regular monitoring. Here, the exogenous H2O2 can act as a signalling molecule and a relatively stable GS dismutation product. It is noted that K+-channels of PNECs can respond to various exogenous and endogenous ligands expressing specific target genes [86,87,94, see also 65]. This allows a better understanding the stability of the cumulative, adaptive and therapeutic effects caused by GS and μMH2O2 in the treatment of patients with bronchial asthma and Parkinson’s disease.

In humans, chronic NAI restriction and / or pathological formation of endogenous ROS (i.e., GS or µMH2O2) can cause dysfunction of the airway epithelium and the development of asthma [49,90,91]. The clinical results of successful treatment of atopic bronchial asthma with “ordinary” NAI [68,76,77] and the significantly higher comparative efficiency of GS inhalations [35-40] may substantiate a crucial role of the inhaled exoROS. For example significant role in the biological and therapeutic activity of AI belongs to the method for ion generating. The comparatively higher therapeutic efficacy of NAI in some early studies (see [68]) can be explained with the use of today banned radioactive α-sources. For example, the absolute predominance of O2●–  (that is, superoxide radicals) in the NAI pool was shown in the paper [20], where α-source was used.

In the context of the above, we note the diffuse located rare NECs in the upper (initial) parts of the respiratory tract. This may indicate that the specific sensitivity of these cells may be involved in forming an assessment of exoROS level as an indicator of air quality. On the contrary, the development of significant pathological changes and the registered death of experimental animals can occur in response to long and intense H2O2 deficiency signalling from NEBs. For example, as a result of prolonged blocking of K+-channels by a high content of PAI due to deprivation of NAI in the air (see above). Thus, GS can indirectly act as a regulator of lung function through respirable µMH2O2 [69]. In contrast, an increase in [O2●– ] in the respiratory air can serve as a signal to reduce pulmonary ventilation. This can lead to a decrease in the formation of endogenous ROS and, as a result, to a decrease in the rate of aging [70].

The peroxide hypothesis also allows for the first time to substantiate a modern explanation of the biochemical effect of PAI. Unlike NAI, many types of positively charged ions can penetrate into the lungs [4]. This may be particularly important in terms of deficiency or deprivation of NAI, where there take place an absolute predominance of PAI [17,48]. In humans, unlike NAI inhalations of PAI induce spastic attaks in normal infants, cancel the therapeutic effects of NAI on patients with spastic bronchitis, cause tachypnea in infants [89] and aggravate the response of asthmatic children to exercise [92].

We can assume several mechanisms of PAI participation in the regulation of the conformational state of K+-channels. One of them is electrostatic neutralization of O2●–  in the upper respiratory tract (nose, larynx, perhaps trachea). The other may be associated with PAI penetration into the respiratory tract and into the lungs and increased depolarization of the K+-channels both in the bronchi and lungs. The consequence of the receptor cells excitation may be increased secretion of 5-HT in the lungs. This latter is reflected in the hypothesis about the role of serotonin – the second most common hypothesis about the biological activity of air ions [78,79,80,81,82,83,84]. The cause of dysfunction in the airway epithelium and the development of asthma can be various external factors (bad ecology, smoking), whose active products are able to penetrate into the lungs [49].

The effects of PAI, usually undesirable or even dangerous, are not related to the presence of GS or H2O2 in them. At the same time, along with the rhythmic fluctuations of exoGS and μMH2O2, PAI are able to influence the rhythmic changes in the depolarization level of the the K+-channel cell membrane during respiration. Thus, the PAI electric charges together with exoH2O2 can serve as peripheral components of the PO2 oscillator – regulator in the lungs and [O2] in the blood. When considering the described biochemical effects of PAI in the lungs, be taking into account the local MAO-dependent metabolism of secreted 5-HT and formation of endogenous H2O2 as a product of these reactions.

The peroxide hypothesis allows predicting the new biological and therapeutic properties of GS and μMH2O2

Our experience shows that this concerns both the biological effects and the therapeutic use of exoROS discussed in this article. Here we present some of the new biological and therapeutic effects of GS and µMH2O2 predicted on the basis of a hypothesis. We will also present the effects of exoROS, which have shown much more pronounced biological or therapeutic results than some previously known uses of NAI. Examples include treatment of bronchial asthma and the pain (see above).

The main biological and clinical effects of O2– , GS and μMH2O2 on the cells, biological models as well mammals and humans, studied by Doctor of Biophysics and Physiology N. Goldstein, Chemist R. Goldstein and colleagues in the years 1970–2019 are listed below. This list does not include our physical and chemical studies of the gaseous ions in the years 1980-1990. Results of these studies are reported in the papers [16,17].

Central and / or predominantly central effects

  • An increase in BBB permeability for drugs and metabolites;
  • Activation of the hypothalamic-pituitary complex;
  • Potentiation of analgesic action of analgesics;
  • Modulation of the odor perception time threshold;
  • Sensitization of the tongue taste buds;
  • Tolerance increasing to nitric oxide NO;
  • Reducing the toxic effects of MPTP on brain structures;
  • Control of the number and functional state of bronchial APUD cells;
  • Reducing of endogenous oxidative stress.

Examples of therapeutic use of GS and μMH2O2

  • Treatment of atopic bronchial asthma (GS; three clinical studies);
  • Treatment of Parkinson’s disease and forms of Parkinsonism (GS; μMH2O2: mono- and adjuvant therapy);
  • Potentiation of analgesics in the treatment of pain (GS; experimental and clinical pilot studies);
  • Treatment of drug addiction and withdrawal (μMH2O2; clinical pilot study);
  • Treatment of cerebral palsy (μMH2O2; clinical pilot study);
  • Treatment of psoriasis (GS; nonsystematic observations).

Some effects at the cellular level

  • Species-dependent sensitivity of microorganisms to exoROS;
  • Increase of the yeast S. cerevisiae resistance to rehydration;
  • Macrophage chemotaxis control.

CONCLUSION

The considerations and facts presented in this article were summarized by the authors on the basis of almost 50 years of their own and other studies of atmospheric and artificial gaseous ions. Thus, the new concept unites at the level of modern knowledge most of the results of research of air ions over the past decades.

The central idea of the new concept is based on the understanding of the dual nature of the O2–  ion as the key ion and as the only radical in the general pool of NAIs, namely, of the superoxide radical O2●– .This approach has greatly expanded the understanding of the specifics and mechanisms of the biological activity of exogenous airborn products O2●–  and μMH2O2 as an exoROS. Awareness of the constant and inevitable presence of harmful, from the point of view of modern knowledge, ROS in the habitat of biota will inevitably lead to a better understanding of the realistic role of NAI and exoROS at all levels of living matter.

Despite the obvious initial interest regarding air ions in the first half of the last century, the both cumulative scientific and practical results of almost 120 years of biological research concerning inhaled air ions were much weaker than the effort expected. Until recently, physics and biology and medicine could not overcome the pressure of dogma about the decisive role of electric charge in the biological effects of an absolute quantitative minority of air components. Therefore, the article entitled: “The ionic effect – how air electricity controls your life and health” did not cause confusion in its time [66].

The main difference between the exoROS effects described in this article and the “ordinary” NAIs is in the crucial role of μMH2O2 as the molecular product of exoO2●–  dismutation. Based on this, the hypothesis regards inhaled μMH2O2 as an exogenous ligand vor the K+-channel of neuroepithelial cells in the respiratory tract and of small organs in the lungs. Carotid bodies in blood vessels may have a similar function. Our data regarding the safety and therapeutic efficiency of nasal exposures by the O2●–  anion-radicals and μMH2O2 confirm McCord’s opinion on superoxide a quarter of a century ago:“Active oxygen intermediates, including superoxide, are capable of inflicting severe damage to tissues. At the same time, these species serve as important physiological signals and play vital protective roles. Is superoxide radical good or bad? The question is an oversimplification. It is either and both, depending on where, when, and how much is produced….Our view is much clearer than it was two decades ago, but we have probably seen only the tip of the iceberg” [72].

In the same year radiobiologist A.M. Kuzin wrote:“… the beneficial effect of ultra-low doses of any factor harmful at high doses was particularly pronounced in cases where the factor being studied was constantly present in the environment … and accompanied all stages evolution of living organisms” [73]. This is certainly applicable to O2●–  and H2O2 since even small doses of ionizing radiation are a natural source of ROS in the atmosphere and world ocean waters.

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