Next Article in Journal
Generation and Characterization of HDV-Specific Antisera with Respect to Their Application as Specific and Sensitive Research and Diagnostic Tools
Previous Article in Journal
Codon Usage Bias in Human RNA Viruses and Its Impact on Viral Translation, Fitness, and Evolution
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Viruses
Volume 17
Issue 9
10.3390/v17091219
viruses-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Hypochlorous Acid (HOCl) as a Promising Respiratory Antiseptic

by
Michael Winter
1,
Dirk Boecker
2 and
Wilfried Posch
3,*
1
Team Winter Kompetenztraining, 1030 Vienna, Austria
2
TOTO Consulting LLC, Campbell, CA 95080, USA
3
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Schöpfstrasse 41/R311, 6020 Innsbruck, Austria
*
Author to whom correspondence should be addressed.
Viruses 2025, 17(9), 1219; https://doi.org/10.3390/v17091219
Submission received: 21 July 2025 / Revised: 1 September 2025 / Accepted: 3 September 2025 / Published: 7 September 2025
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
Browse Figure
Versions Notes

Abstract

The COVID-19 pandemic has inflicted unprecedented pressure on communities and healthcare systems around the world. An outstandingly broad and intensive investigation of possible therapeutic interventions is currently taking place to prevent similar future threats to the global population. Investigating the related mechanisms of action is often complex and time consuming. Moreover, research on biochemical interactions of new drugs involves a considerable amount of effort, consequently bearing inherent financial and operational risks for pharmaceutical companies. An interesting approach to counteract colonization and infection is the concept of antiseptic treatment in vivo. Antiseptics are cost-effective and globally accessible, due to their ease of production, transportation and handling. A broad spectrum of active agents with different properties is readily available. One of these substances is hypochlorous acid (HOCl), which is also a naturally occurring biocidal agent and as such part of the innate immune system. Its successful history of medical use in wound treatment, combined with low cytotoxicity and documented efficacy against various pathogens, suggests that HOCl might be an effective agent for treating the respiratory mucosa. This could potentially enable therapeutic inhalation for combating bacterial infections and viral pathogens such as human respiratory syncytial, influenza, and SARS-CoV-2 viruses, which will be discussed in the present article.

1. Introduction

The pursuit of novel antibiotic treatment options to mitigate the worldwide problem of growing bacterial resistance has become increasingly difficult and cost-intensive in recent years [1]. Also, the efficacy of antibiotics and other pharmacological interventions mostly depends on the correct diagnosis of the underlying pathogen.
In comparison, an antiseptic approach is limited to mainly external application, but more resilient against diagnostic ambiguities and errors, due to its agnostic mechanism of action [2,3].
Its broad efficacy is therefore advantageous in less developed areas with limited access to medical infrastructure. Concurrently, in suitable fields of application it may prove helpful even in advanced medical institutions by exerting protective action against various nosocomial pathogens [4], with the possible benefit of containing resistance development.
A variety of existing antiseptic agents exhibit notable resilience against microbial resistance, characterized by their continuously effective reduction in bacterial loads in vitro [5,6]. Due to their broad spectrum of action, antiseptic treatments also provide the advantage to be utilized against viral and fungal infections [7,8].
Thus, especially considering emerging viruses and the COVID-19 pandemic, it would be pertinent to investigate the potential applications of these antiseptic agents in treating common infections, like those affecting the respiratory mucosa. Understanding their effectiveness in such contexts could provide valuable insights into expanding their therapeutic utility beyond conventional uses.
However, in a potential new scientific field of antiseptic treatment of respiratory tract infections, it is crucial to rigorously evaluate safety concerns. For these efforts it is reasonable to re-examine the respiratory pathways, for their distinct tissue properties, characteristics in microbiome and systemic functional contributions. Depending on the area of mucosal application, a variety of different antimicrobial and antiviral agents may be considered [9,10].

2. Antiseptics of Interest

In their recommendations in the context of the COVID-19 pandemic [11], the German Society for Hospital Hygiene (DGKH) mentioned various antiseptic agents, including two pre-exposure prophylactic agents used at the University Medicine Greifswald, povidone-iodine (PVP-I) and essential oils:
In the area of medical antiseptics, povidone-iodine (PVP-I) has been used internationally in tolerable concentrations between 0.23% and 1.25% inside the nose and mouth for prophylaxis, and could be effective in early treatment [11,12]. A mouthwash with essential oils is commercially available with and without ethanol, and has achieved relevant log reductions in vitro [11,13]. For sensitive individuals it is possible to gargle with green tea or aronia juice, combined with the use of saline solutions or carragelose [14] for the nasal passages.
However, not all common antiseptics were reported as effective against SARS-CoV-2. Common antiseptic mouthwashes based on hydrogen peroxide (H2O2), polyhexanide and octenidine were described as not sufficiently effective against SARS-CoV-2 in vitro, but remain an interesting alternative for other types of infection [10,11].
The DGKH outlined its perspective on sodium hypochlorite and HOCl. A comparative in vitro study with encouraging results of an HOCl/stabilized hypochlorite mouthwash was mentioned [11,13]. Also, a combination of sodium hypochlorite (NaOCl) and HOCl with a gel matrix achieved a log reduction of 2.21 within 30 s, rendering it the only nasal spray with a potentially clinically relevant log reduction in SARS-CoV-2 in another comparative study [11,15]. The authors recommended it as a post-exposure prophylaxis, but suggested that tolerability of long-term use of NaOCl needs clarification.
Although not mentioned in the DGKH paper, the HOCl derivative N-chlorotaurine (NCT) formed by reaction with taurine might be considered as well, and has been suggested to be a suitable agent for respiratory disinfection [16].
While several agents were discussed in the DGKH publication, HOCl may be considered particularly interesting, due to its natural presence in the respiratory tract [17] and its reported efficacy.

3. HOCl

In general, an ideal antiseptic agent should possess attributes such as low cell toxicity, sufficient efficacy against a broad spectrum of pathogens, and should be non-allergenic as well as non-irritating. Current research demonstrated all of these favorable characteristics for HOCl [3,18], a compound integral to the innate immune system.

3.1. Key Role of HOCl in the Innate Immune System

White blood cells, particularly neutrophils and monocytes, produce reactive oxygen species like H2O2 and HOCl upon cell activation. This can be induced through the activation of PRRs like Toll-like receptors, Fc receptor binding and several other mechanisms [19].
HOCl is a weak acid but a strong oxidizing agent. It interacts with structural components of viruses and bacteria, making it a crucial endogenous molecule for effective phagocytosis [3]. Macrophages and microglia cells produce HOCl from intracellular NaCl using the myeloperoxidase enzyme system. The reactive HOCl is then released to oxidize the invading pathogen, and ultimately converted back to NaCl [20].
In biological systems, HOCl can be regarded as the most effective and most common oxidizing agent. It is one of the foremost endogenous molecules for effective phagocytosis of invading bacteria or viruses [21].

3.2. Production of Exogenous HOCl

HOCl has been broadly used in therapeutic applications, as well as for disinfection of surfaces, water, food and room air [22]. Different production methods of HOCl have been established, to meet the requirements of their respective industrial use.
HOCl solutions can be produced through 2 methods: either direct injection of gaseous chlorine into water, or electrolysis of hydrochloric acid or an aqueous solution of sodium chloride. Several factors influence the production and efficiency of electrolyzed water, including water and electrolyte properties, electrode material, current, storage, and application factors. A comprehensive overview is given by Ampiaw et al. [23].
In aqueous solutions under physiological conditions the pair of HOCl with its conjugated base OCl− represents the potent oxidizing redox system [E0’ = +0.9 (OCl−); E0’ = +1.48 V (HOCl)]. At a pH of about 7.5, the concentration of HOCl and its correlated base form OCl− are approximately equal [24,25].
At pH 5 HOCl is the dominant oxidizing agent. Lowering the pH of HOCl/OCl− solutions below 5 increases the oxidation potential monotonically, caused by a proportional increase in the Cl2 (aq) concentration (extensively studied via Raman spectroscopy by Cherney et al. [26]).

3.3. Reaction Mechanisms of Externally Applied HOCl

In wound treatment, HOCl at suitable concentrations supports the healing process upon application. Research has demonstrated its beneficial effects on healing mechanisms of the mucosa and other tissue types, rendering it an effective ingredient and possible future gold standard for topical wound care solutions [27].
The chemical reaction of HOCl with endothelial structures deactivates microbes by oxidizing their cellular components, such as proteins, lipids, and DNA, leading to cell death [20]. This reaction is non-specific and effectively kills a wide range of microbes, including bacteria, viruses, and fungi.
Furthermore, HOCl stimulates the production of neutrophil extracellular traps (NETs), which can trap and kill microbes [28,29].
Besides its direct biocidal activities HOCl is also involved in complement-mediated immunity, a synergistic acting protein cascade of the innate immune system that helps eliminate pathogens and initiate inflammation [20,21,30]. HOCl activates immune cells, such as macrophages, recruiting them to the site of infection.
Finally, it promotes the abundant presence of the antimicrobial acting N-chlorotaurine (NCT) in the extracellular medium. This reversible reaction modulates the oxidizing capability of HOCl through the formation of the less reactive oxidant NCT [31].
Due to these antimicrobial properties, HOCl is expected to exert significant influence on the microbiome of the application area. Therefore, it is important to investigate possible adverse systemic effects of its use on the respiratory mucosa, particularly in emerging applications such as inhalation.

4. Systemic Relevance of Respiratory Microbiome Reduction

4.1. Mucosal Environment and Reactive Oxygen Species

In healthy individuals, upper airways are relatively robust and typically host a diverse and balanced array of microbial species, collectively known as the mucosal microbiome [32,33].
Changes in its equilibrium can be potentially problematic. Accumulations of specific bacterial organisms are often linked to cardiovascular diseases like hypertension and various forms of dementia, among them Chlamydia pneumoniae [34] in the pharynx, or Treponema denticola [35] and Porphyromonas gingivalis [36] in the oral cavity. Bacterial colonization leading to caries and periodontitis contributes to a broad spectrum of systemic disorders [37].
The metabolic activity of the mucosal microbiome contributes to a variety of essential systemic mechanisms. Some of the factors possibly being impacted by antiseptic intervention are vitally important, like the bioavailability of nitric oxide (NO), through which the mucosal microbiome likely participates in the regulation of blood pressure [38,39] and the sleep–wake cycle [40].
The respiratory epithelium employs mucociliary mechanisms to continually clear inhaled particles and pathogens by constant movement of mucus to the oropharynx and eventual dispatch through the digestive system [41]. Bronchial tissue and its secretions contain a range of immune cells, including dendritic cells, macrophages and highly mobile neutrophils, which all contribute to the defense against respiratory infections by producing HOCl and other reactive oxygen species (ROS), and thus rendering HOCl an inherent part of the mucosal environment [42,43].
Apart from these immune cells, several types of other cells of the ciliated epithelium also recognize bacterial components through specific PRR-receptors on their surface. Activation of these receptors triggers signaling pathways, which leads to the release of inflammatory mediators like cytokines and chemokines [44,45]. One of these cytokines is interleukin-6 (IL-6), which acts as a pyrogen and plays an important role in the immune response during inflammation and infection. In addition to epithelial cells, it is also produced by fibroblasts and macrophages [46].
Epithelial cells contribute directly to the control of microbial contamination, producing antimicrobial peptides, surfactant proteins, immunoglobulins and ROS including HOCl [3,17,47,48].
As a result of the combined effect of this interplay, healthy microbiome of lower airways typically shows similar microbial community variation with significantly lower log counts [49]. Its metabolic products likely exert only minor effects on systemic functions.

4.2. Implications for Inhalation

Inhalation of supplementary exogenous HOCl is anticipated to have minimal impact on oral microbial biomass compared to mouthwashes, due to its minor concentration and dosage. In the lower airways, microbial counts are generally low. Additionally, antiseptic treatments are generally less specific and therefore less likely to inflict dysbiosis than current antibiotics [50]. Therefore, regarding the respiratory microbiome, antiseptic inhalation is not expected to pose greater concerns than established antibacterial treatments such as antimicrobial mouthwashes targeting the pharyngeal mucosa.
It may instead be anticipated to provide a favorable effect in the respiratory tract similar to toothpaste [51] and some mild antiseptic mouthwashes [52], evening out dysbiosis while counteracting infection.

5. HOCl-Containing Products

An increasing variety of HOCl-containing health products is available throughout Europe. Depending on their intended use, they are predominantly approved as medical devices in the appropriate class, as shown in Table 1.
In the United States, several medical devices formulated with HOCl have FDA 510(k) clearance [53,54]. Some HOCl-based products have entered dermatology [55], and more recently the consumer cosmetics market, receiving growing public attention [56].
Table 1. Examples of HOCl-based medical devices and health products in Europe.
Table 1. Examples of HOCl-based medical devices and health products in Europe.
Product NameManufacturerCountryTotal Free Chlorine (ppm)Medical Device ClassApprovalRecommended Use
Plasma Liquid® Nasal SprayRegeno GmbHMannheim, Germany<600 [57]IIaCE markedCleansing and moisturizing the nasal mucosa
Granudacyn® Mouth WashMölnlycke Health Care GmbHDüsseldorf, Germany105 [58]IIaCE markedMouthwash for oral hygiene and pathogen reduction
Oji Biosafety Room Air Disinfection Systemoji Europe GmbH, Nauen, Germany<0.5 (regulatory limit [59], *) not applicablenot applicableLong-term air disinfection to reduce airborne pathogens
Veriforte® Wound Irrigation SolutionP.G.F. Industry Solutions GmbHElixhausen, Austria93 [58]IIbCE markedCleansing and irrigation of acute and chronic wounds
Actimaris® Nasal SprayActiMaris AGAppenzell, Switzerland440 [60]ICE markedCleansing and moisturizing the nasal mucosa
Hydroliq Fogging SolutionHydroliq AGLucerne, Switzerland<0.5 (regulatory limit [59], *)not applicablenot applicableSurface and air disinfection in various settings
Microdacyn60® Wound Care SolutionOculus Innovative Sciences Netherlands B.V.Delft, Netherlands80 [58]IIbCE markedCleansing and irrigation of acute and chronic wounds
Spectricept™ Skincare SolutionSpectrumX Direct LimitedKnutsford, United KingdomunknownIIaCE markedSkincare solution for cleansing and moisturizing
OraWize+ Mouthwash/Dental RinseTec-SafeMaccelsfield, United Kingdom100–200 [13]IIaCE markedMouthwash for oral hygiene and pathogen reduction
Briotech Topical Skin SprayBriotech EUVantaa, Finlandunknownnot applicableunknownTopical spray for cleansing and moisturizing the skin
* Reference occupational exposure limit for chlorine in workplace air (Germany).

6. Dosage and Safety Considerations on HOCl-Inhalation

The concentrations of HOCl vary significantly depending on the intended application. It is important to consider pH and the ratio between HOCl and other ROS in these products, especially those produced through electrolysis, with the goal of ensuring that HOCl, the more effective and less cytotoxic component, is the predominant species [61,62].
In the context of inhalation, recent evidence notably suggests that aerosolized base fluids containing up to ≈5.72 mM (300 ppm) HOCl at a pH of 6.5 do not affect respiratory tissue, cellular viability, or morphology [63,64].
While it is commonly presumed that droplet size of aerosols defines the maximum bronchiolar propagation range, from a physical perspective some outgassing from droplets in their proximity is to be expected during inhalation. Traces of HOCl in its gas phase will therefore likely reach the pulmonary alveoli, along with some very small droplets under 1 μm [65,66]. Alveolar membranes in the human lung are very delicate with a minimum thickness of less than 1 μm [67,68], underlining the diligence of choosing the lowest effective concentration of any oxidizing agents applied.
Biological HOCl concentrations within inflamed tissue can reach micromolar levels of about 200 μM (≈10.5 ppm) [69], contributing to oxidative stress and subsequently host cell damage during chronic inflammation. The mucosa of the respiratory tract and the lung parenchyma counteract excessive ROS damage by a variety of mechanisms, utilizing antioxidant substances like ascorbic acid, α-tocopherol, glutathione and taurine [70,71], in accordance with the complex role played by NO [72].
High second-order rate constants, in the range of 107 to 108 M−1·s−1, are observed for reactions of HOCl with cysteine and methionine [73], as well as thiocyanate (SCN−) [74]. The reaction with SCN− leads to the formation of hypothiocyanite (OSCN−), a mild oxidant with synergistic antimicrobial properties [75].
A modest amount of oxidative stress is thought to be beneficial rather than harmful to human cells, inducing a hormetic response [76,77], by which intracellular adaptive mechanisms to low-level stressors may potentially increase cellular lifespan and health span.
Depending on HOCl concentration, different mechanisms of action against pathogens have been discussed. Some authors have proposed that concentrations in the micromolar range impact bacterial DNA synthesis, while concentrations in the millimolar range result in membrane disruption [78,79].
ROS inducers have been suggested as a possible intervention against viral infections, including SARS-CoV-2, by impairment of RNA integrity [80]. On the other hand, oxidative stress also contributes to viral pathogenesis and exerts pro-infectious effects [81]. For example, recent research has proposed enhanced ACE2-binding by SARS-CoV-2 due to oxidative conditions locally facilitating the formation of disulfide bonds [82].
However, HOCl rapidly compromises and cleaves disulfide bonds at very low concentrations [83,84]. This may constitute an interesting virucidal mechanism by external HOCl through rapid cysteine interaction, overoxidation, and cleavage of solvent-exposed disulfide bridges, for example, between cysteine residues C480 and C488 [85] in the SARS-CoV-2 receptor-binding motif (see Figure 1).
Conceivable additional targets within the spike glycoprotein include the accessible cysteine residues and disulfide bond at C391-C525 and the bridge at C379-C432 [87], as well as other reactive residues such as methionine, histidine, tyrosine, and tryptophan [88].
A similar approach to virucidal effects by low supplemental HOCl-concentrations may be feasible in human respiratory syncytial virus (RSV) as well, for example through the oxidation of the structurally critical and sterically accessible residues C69/C212 [89] and C37/C439 [90], as well as cleavage of their respective disulfide bridges, in the RSV F protein (PDB entry 4JHW [91]).
Compared to SARS-CoV-2 and RSV, influenza virions appear to be even more susceptible to oxidation, due to their delicate lipid layer and high dependance on exposed disulfides [92]. Correspondingly, influenza A strains exhibited high vulnerability [93], and less resistance than SARS-CoV-2 [94], in fogging experiments with low-dose HOCl.
For an inhalative intervention, a conservative and practical strategy would involve using concentrations close to physiological levels, aiming for a target concentration of approximately 200 μM. Experimental studies suggest a considerable loss in free chlorine concentration of airborne electrolyzed water during spraying, reaching almost 50% decrease during a travel distance of 25 cm [95].
Furthermore, dilution at the target site, as well as reactive consumption by surfactant proteins, thiol groups and other reactive species is to be expected.
However, under infectious and inflammatory conditions, the buffering capacity of the airway lining fluid may be compromised [96]. In an experimental decontamination effort or early treatment attempt, it therefore seems reasonable to employ a maximum concentration of approximately 500 μM (≈26 ppm) HOCl as the base fluid for aerosolization, and thus aiming for mild antimicrobial effects by targeted oxidation of sterically exposed amino acid residues, rather than classical antiseptic log reduction through membrane disruption.
This strategy involves comparatively low external HOCl concentrations, however it may induce favorable secondary biochemical reactions in situ, which lead to a selectively increased oxidative potential in close proximity of some pathogens (discussed in Section 7). Additionally, physiological temperature levels are expected to significantly enhance HOCl reactivity in vivo and further improve antimicrobial action [97].

7. Discussion

The possibility of administering antiseptic treatments repeatedly in quick succession (e.g., 3 or 4 times per day), with the goal of reducing viral and bacterial loads over prolonged periods, may help alleviate the metabolic burden of infection and improve clinical efficacy. This strategy relies to a significant extent on low cytotoxicity and side-effects, which is an established advantage of HOCl in wound treatment [3], since the majority of publications reports low cytotoxicity [98] in wound treatment and no side effects in peritoneal lavage [99].
While other antiseptic agents like benzalkonium chloride or triclosan may induce cross-resistance in some bacterial species, there is no documentation of resistance facilitated by NaOCl [100].
There is some evidence for a “trade-off” between antimicrobial efficacy and undesirable effects like decreasing viability of keratinocytes and fibroblasts [58] when HOCl is applied in vitro in certain millimolar concentrations. However—in vivo concentrations of HOCl are normally in a much lower micromolar range.
While HOCl as an oxidative species may initially have beneficial effects in infections, ROS have been documented to play a role in the formation of macrophage extracellular traps [28], with prolonged excess levels contributing to chronic inflammation. Chronic oxidative stress and inflammation in a typically heterogeneous ROS-dominated milieu is widely acknowledged to be detrimental, can promote viral replication [81], and contributes to aging and oncogenesis [101].
Conversely, excessive ROS levels can also induce cancer cell death, and are deliberately exploited in therapeutic approaches such as radiation and chemotherapy [102]. Thus, accurate distinction of oxidative species, concentration, timing and location is a prerequisite for determining the biological outcome.
Interestingly, HOCl was shown to induce apoptosis selectively in malignant cells expressing NADPH oxidase. Selective action against transformed cells apparently depends on the interaction between their NOX1-generated superoxide anions and HOCl, resulting in hydroxyl radicals, which then induce apoptosis [103].
HOCl has been documented to ameliorate nuclear factor-κB-mediated skin diseases in mice [104], and a solution containing HOCl and NaOCl blocked tumorigenic UV-induced inflammatory progression in another murine model [105,106,107].
Recently, HOCl has also shown favorable results in a comparison of oral antiseptics for radiation- or chemotherapy induced mucositis [108]. Furthermore, a recent in vitro study illustrated reduced binding of IL-6 to its receptors following treatment with HOCl, and this reaction with IL-6 receptors showed high reactivity already at 72 µM [109]. Notably, not just HOCl itself, but also its derivative N-chlorotaurine (NCT) is able to downregulate IL-6-dependent pro-inflammatory pathways, which play an important role in clinical conditions like those seen with severe COVID-19 [16,110].
Further clinical research on the possible role of HOCl in the ongoing fight against SARS-CoV-2 was recommended in several recent publications [3,22,111]. A randomized, double-blind, controlled clinical study is currently ongoing in parts of Europe, inquiring into the potential of HOCl-containing nasal spray and mouthwash as an early treatment against COVID-19. It is evaluated if this combined intervention, several times per day over ten days, can reduce viral load, shorten the duration of test positivity or alleviate symptoms [112].
HOCl has been acknowledged as effective against SARS-CoV-2 in vitro by a Japanese NITE special committee, at concentrations of 35 ppm and above [113]. It also inactivated oral pathogens and a SARS-CoV-2 surrogate within 30 s in vitro at low concentrations (45–60 ppm), even in the presence of saliva. In the same study, further tests with a 26 ppm solution still documented encouraging antimicrobial activity by the complete inhibition of Prevotella intermedia [2].
Antiviral efficacy against human norovirus and two surrogate viruses was observed at very low concentrations, with HOCl applied both as a liquid and a fog at 18.8 ppm and above [114].
Efficacy of HOCl against biofilms like those created by Streptococcus mutans and Streptococcus gordonii was documented [115,116], exhibiting its high oxidative reactivity against proteins and peptide bonds. More specific research on its putative potential to inactivate toxins, like bacterial exotoxins or mucosal complement anaphylatoxins [117,118] by topical application is warranted.
Despite their early documentation [79], the remarkable antimicrobial effects of HOCl in regular biological concentrations of only 50 μM (≈2.6 ppm), including the apparently complete inactivation of the growth of E. coli within 5 min in vitro, have not resulted in extensive clinical research to date.
The presence of pathogens correlates with local concentrations of biological ROS. Potential explanations for a higher-than-expected in vivo efficacy of externally applied micromolar HOCl therefore include its possible interaction with locally available biological H2O2 and, like in the beforementioned anti-oncogenetic effect, interaction with local superoxide anions. This may selectively lead to the formation of singlet oxygen and hydroxyl radicals capable of inducing apoptosis in the close proximity of pathogens [103,119]:
HOCl + H2O2 → H2O + 1O2 + H+ + Cl−
HOCl + O2⋅− → ⋅OH + Cl− + O2

8. Conclusions

An experimental clinical strategy for early treatment of a broad range of bacterial and viral infections, including those caused by the Pneumoviridae family like RSV, as well as influenza viruses and SARS-CoV-2 [8,120,121,122], could be based on inhalation, evaluating aerosolized low-dose HOCl solutions of up to 500 μM (≈26 ppm) in controlled trials.
A conservative approach, loosely resembling and supplementing endogenous countermeasures to infections, may presumably be repeated frequently—initially covering a time period similar to the reaction time of the adaptive immune system, aiming to keep microbial or viral replication and log counts low and manageable, until specific antibodies and T-cells have arrived at the infection site.
Therapeutic success of this kind of intervention would likely result in mitigation of clinical symptoms and reduced morbidity rather than PCR test negativity, since impaired and non-reproductive virions or bacteria [123] will still generate positive test results.

Author Contributions

Conceptualization, M.W. and W.P.; resources, M.W., D.B. and W.P.; writing—original draft preparation, M.W., D.B. and W.P.; writing—review and editing, M.W. and W.P.; visualization, M.W.; supervision, W.P.; project administration, W.P.; funding acquisition, W.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Austrian Science Fund (FWF) [DOI 10.55776/P34070].

Acknowledgments

Michael Winter would like to express his deep gratitude for the extraordinarily valuable insights provided by Georg Bauer.

Conflicts of Interest

Michael Winter and Wilfried Posch declare no conflicts of interest. Dirk Boecker is personally acquainted and currently providing pro bono advice to oji Europe GmbH.

References

  1. Butler, M.S.; Henderson, I.R.; Capon, R.J.; Blaskovich, M.A.T. Antibiotics in the clinical pipeline as of December 2022. J. Antibiot. 2023, 76, 431–473. [Google Scholar] [CrossRef] [PubMed]
  2. Tazawa, K.; Jadhav, R.; Azuma, M.M.; Fenno, J.C.; McDonald, N.J.; Sasaki, H. Hypochlorous acid inactivates oral pathogens and a SARS-CoV-2-surrogate. BMC Oral Health 2023, 23, 111. [Google Scholar] [CrossRef] [PubMed]
  3. Boecker, D.; Zhang, Z.; Breves, R.; Herth, F.; Kramer, A.; Bulitta, C. Antimicrobial efficacy, mode of action and in vivo use of hypochlorous acid (HOCl) for prevention or therapeutic support of infections. GMS Hyg. Infect Control 2023, 18, Doc07. [Google Scholar] [CrossRef] [PubMed]
  4. Kiamco, M.M.; Zmuda, H.M.; Mohamed, A.; Call, D.R.; Raval, Y.S.; Patel, R.; Beyenal, H. Hypochlorous-Acid-Generating Electrochemical Scaffold for Treatment of Wound Biofilms. Sci. Rep. 2019, 9, 2683. [Google Scholar] [CrossRef]
  5. Barakat, N.A.; Rasmy, S.A.; Hosny, A.E.D.M.S.; Kashef, M.T. Effect of povidone-iodine and propanol-based mecetronium ethyl sulphate on antimicrobial resistance and virulence in Staphylococcus aureus. Antimicrob. Resist. Infect. Control 2022, 11, 139. [Google Scholar] [CrossRef]
  6. Chen, C.J.; Chen, C.C.; Ding, S.J. Effectiveness of hypochlorous acid to reduce the biofilms on titanium alloy surfaces in vitro. Int. J. Mol. Sci. 2016, 17, 1161. [Google Scholar] [CrossRef]
  7. Hacioglu, M.; Oyardi, O.; Yilmaz, F.N.; Nagl, M. Comparative Fungicidal Activities of N-Chlorotaurine and Conventional Antiseptics against Candida spp. isolated from vulvovaginal candidiasis. J. Fungi 2022, 8, 682. [Google Scholar] [CrossRef]
  8. Tamaki, S.; Bui, V.N.; Ngo, L.H.; Ogawa, H.; Imai, K. Virucidal effect of acidic electrolyzed water and neutral electrolyzed water on avian influenza viruses. Arch. Virol. 2014, 159, 405–412. [Google Scholar] [CrossRef]
  9. Kamal Arefin, M.; Banu, S.S.; Nasir Uddin, A.K.M.; Nurul Fattah Rumi, S.K.; Khan, M.; Kaiser, A.; Arafat, M.S.; Chowdhury, J.A.; Khan, M.A.S.; Hasan, M.J. Virucidal Effect of Povidone Iodine on SARS-CoV-2 in Nasopharynx: An Open-Label Randomized Clinical Trial. Indian. J. Otolaryngol. Head. Neck Surg. 2022, 74, 3283–3292. [Google Scholar] [CrossRef]
  10. Meister, T.L.; Brüggemann, Y.; Todt, D.; Conzelmann, C.; Müller, J.A.; Groß, R.; Münch, J.; Krawczyk, A.; Steinmann, J.; Steinmann, J. Virucidal efficacy of different oral rinses against severe acute respiratory syndrome Coronavirus 2. J. Infect. Dis. 2020, 222, 1289–1292. [Google Scholar] [CrossRef]
  11. Kramer, A.; Eggers, M.; Exner, M.; Simon, A.; Steinmann, E.; Zwicker, P. Recommendation of the German Society of Hospital Hygiene (DGKH): Prevention of COVID-19 by virucidal gargling and virucidal nasal spray—Updated version April 2022. GMS Hyg. Infect. Control 2022, 17, Doc13. [Google Scholar] [CrossRef]
  12. Choudhury, M.I.M.; Shabnam, N.; Ahsan, T.; Kabir, M.S.; Md Khan, R.; Ahsan, S.A. Effect of 1% Povidone Iodine Mouthwash/Gargle, Nasal and Eye Drop in COVID-19 patient. Biores. Commun. 2021, 7, 919–923. [Google Scholar] [CrossRef]
  13. Davies, K.; Buczkowski, H.; Welch, S.R.; Green, N.; Mawer, D.; Woodford, N.; Roberts, A.D.G.; Nixon, P.J.; Seymour, D.W.; Killip, M.J. Effective in vitro inactivation of SARS-CoV-2 by commercially available mouthwashes. J. Gen. Virol. 2021, 102, 001578. [Google Scholar] [CrossRef] [PubMed]
  14. Ludwig, M.; Enzenhofer, E.; Schneider, S.; Rauch, M.; Bodenteich, A.; Neumann, K.; Prieschl-Grassauer, E.; Grassauer, A.; Lion, T.; Mueller, C.A. Efficacy of a Carrageenan nasal spray in patients with common cold: A randomized controlled trial. Respir. Res. 2013, 14, 124. [Google Scholar] [CrossRef] [PubMed]
  15. Meister, T.L.; Todt, D.; Brüggemann, Y.; Steinmann, J.; Banava, S.; Brill, F.H.H.; Pfaender, S.; Steinmann, E. Virucidal activity of nasal sprays against severe acute respiratory syndrome coronavirus-2. J. Hosp. Infect. 2022, 120, 9–13. [Google Scholar] [CrossRef]
  16. Marcinkiewicz, J.; Nagl, M.; Kyriakopoulos, A.; Walczewska, M.; Skóra, M.; Skalska, P. Current Opinion on the Therapeutic Capacity of Taurine-Containing Halogen Derivatives in Infectious and Inflammatory Diseases. In Taurine 12; Advances in Experimental Medicine and Biology; Schaffer, S.W., El Idrissi, A., Murakami, S., Eds.; Springer: Cham, Switzerland, 2022; Volume 1370, pp. 83–98. [Google Scholar] [CrossRef]
  17. Hiemstra, P.S.; McCray, P.B.; Bals, R. The innate immune function of airway epithelial cells in inflammatory lung disease. Eur. Respir. J. 2015, 45, 1150–1162. [Google Scholar] [CrossRef]
  18. Küster, I.; Kramer, A.; Bremert, T.; Langner, S.; Hosemann, W.; Beule, A.G. Eradication of MRSA skull base osteitis by combined treatment with antibiotics and sinonasal irrigation with sodium hypochlorite. Eur. Arch. Oto-Rhino-Laryngol. 2016, 273, 1951–1956. [Google Scholar] [CrossRef]
  19. Nguyen, G.T.; Green, E.R.; Mecsas, J. Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Front. Cell Infect. Microbiol. 2017, 7, 373. [Google Scholar] [CrossRef]
  20. Andrés, C.M.C.; Pérez de la Lastra, J.M.; Juan, C.A.; Plou, F.J.; Pérez-Lebeña, E. Hypochlorous Acid Chemistry in Mammalian Cells—Influence on Infection and Role in Various Pathologies. Int. J. Mol. Sci. 2022, 23, 10735. [Google Scholar] [CrossRef]
  21. Ulfig, A.; Leichert, L.I. The effects of neutrophil-generated hypochlorous acid and other hypohalous acids on host and pathogens. Cell. Mol. Life Sci. 2021, 78, 385–414. [Google Scholar] [CrossRef]
  22. Block, M.S.; Rowan, B.G. Hypochlorous Acid: A Review. J. Oral Maxillofac. Surg. 2020, 78, 1461–1466. [Google Scholar] [CrossRef]
  23. Ampiaw, R.E.; Yaqub, M.; Lee, W. Electrolyzed water as a disinfectant: A systematic review of factors affecting the production and efficiency of hypochlorous acid. J. Water Process Eng. 2021, 43, 102228. [Google Scholar] [CrossRef]
  24. USDA. Hypochlorous Acid. Technical Evaluation Report. 2015. Available online: https://www.ams.usda.gov/sites/default/files/media/Hypochlorous%20Acid%20TR%2008%2013%2015.pdf (accessed on 6 April 2024).
  25. Briotech, Inc. Application for Inclusion in the 2021 WHO Essential Medicines List. 2021. Available online: https://www.who.int/groups/expert-committee-on-selection-and-use-of-essential-medicines/23rd-expert-committee/a18-hypochlorous (accessed on 4 September 2025).
  26. Cherney, D.P.; Duirk, S.E.; Tarr, J.C.; Collette, T.W. Monitoring the Speciation of Aqueous Free Chlorine from pH 1 to 12 with Raman Spectroscopy to Determine the Identity of the Potent Low-pH Oxidant. Appl. Spectrosc. 2006, 60, 764–772. [Google Scholar] [CrossRef]
  27. Gold, M.H.; Andriessen, A.; Bhatia, A.C.; Bitter, P.; Chilukuri, S.; Cohen, J.L.; Robb, C.W. Topical stabilized hypochlorous acid: The future gold standard for wound care and scar management in dermatologic and plastic surgery procedures. J. Cosmet. Dermatol. 2020, 19, 270–277. [Google Scholar] [CrossRef]
  28. Rayner, B.S.; Zhang, Y.; Brown, B.E.; Reyes, L.; Cogger, V.C.; Hawkins, C.L. Role of hypochlorous acid (HOCl) and other inflammatory mediators in the induction of macrophage extracellular trap formation. Free Radic. Biol. Med. 2018, 129, 25–34. [Google Scholar] [CrossRef]
  29. Islam, M.d.M.; Takeyama, N. Role of Neutrophil Extracellular Traps in Health and Disease Pathophysiology: Recent Insights and Advances. Int. J. Mol. Sci. 2023, 24, 15805. [Google Scholar] [CrossRef] [PubMed]
  30. Biedroń, R.; Konopiński, M.K.; Marcinkiewicz, J.; Józefowski, S. Oxidation by Neutrophils-Derived HOCl Increases Immunogenicity of Proteins by Converting Them into Ligands of Several Endocytic Receptors Involved in Antigen Uptake by Dendritic Cells and Macrophages. PLoS ONE 2015, 10, e0123293. [Google Scholar] [CrossRef]
  31. Zgliczyński, J.M.; Stelmaszyńska, T.; Domański, J.; Ostrowski, W. Chloramines as intermediates of oxidation reaction of amino acids by myeloperoxidase. Biochim. Biophys. Acta (BBA) Enzymol. 1971, 235, 419–424. [Google Scholar] [CrossRef]
  32. Sender, R.; Fuchs, S.; Milo, R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol. 2016, 14, e1002533. [Google Scholar] [CrossRef]
  33. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012, 486, 207–214. [Google Scholar] [CrossRef] [PubMed]
  34. Campbell, L.A.; Kuo, C.C. Chlamydia pneumoniae—An infectious risk factor for atherosclerosis? Nat. Rev. Microbiol. 2004, 2, 23–32. [Google Scholar] [CrossRef] [PubMed]
  35. Ide, M.; Harris, M.; Stevens, A.; Sussams, R.; Hopkins, V.; Culliford, D.; Fuller, J.; Ibbett, P.; Raybould, R.; Thomas, R.; et al. Periodontitis and Cognitive Decline in Alzheimer’s Disease. PLoS ONE 2016, 11, e0151081. [Google Scholar] [CrossRef]
  36. Dominy, S.S.; Lynch, C.; Ermini, F.; Benedyk, M.; Marczyk, A.; Konradi, A.; Nguyen, M.; Haditsch, U.; Raha, D.; Griffin, C.; et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv. 2019, 5, eaau3333. [Google Scholar] [CrossRef]
  37. Kinane, D.F.; Stathopoulou, P.G.; Papapanou, P.N. Periodontal diseases. Nat. Rev. Dis. Primers 2017, 3, 17038. [Google Scholar] [CrossRef]
  38. Lundberg, J.O.; Weitzberg, E.; Gladwin, M.T. The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug Discov. 2008, 7, 156–167. [Google Scholar] [CrossRef] [PubMed]
  39. Tribble, G.D.; Angelov, N.; Weltman, R.; Wang, B.Y.; Eswaran, S.V.; Gay, I.C.; Parthasarathy, K.; Dao, D.H.V.; Richardson, K.N.; Ismail, N.M.; et al. Frequency of tongue cleaning impacts the human tongue microbiome composition and enterosalivary circulation of nitrate. Front. Cell. Infect. Microbiol. 2019, 9, 434270. [Google Scholar] [CrossRef]
  40. Cespuglio, R.; Amrouni, D.; Meiller, A.; Buguet, A.; Gautier-Sauvigné, S. Nitric oxide in the regulation of the sleep-wake states. Sleep. Med. Rev. 2012, 16, 265–279. [Google Scholar] [CrossRef]
  41. Fahy, J.V.; Dickey, B.F. Airway Mucus Function and Dysfunction. N. Engl. J. Med. 2010, 363, 2233–2247. [Google Scholar] [CrossRef]
  42. Worbs, T.; Hammerschmidt, S.I.; Förster, R. Dendritic cell migration in health and disease. Nat. Rev. Immunol. 2017, 17, 30–48. [Google Scholar] [CrossRef]
  43. Whitsett, J.A.; Alenghat, T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat. Immunol. 2015, 16, 27–35. [Google Scholar] [CrossRef] [PubMed]
  44. Akira, S.; Uematsu, S.; Takeuchi, O. Pathogen Recognition and Innate Immunity. Cell 2006, 124, 783–801. [Google Scholar] [CrossRef] [PubMed]
  45. Kawai, T.; Akira, S. The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nat. Immunol. 2010, 11, 373–384. [Google Scholar] [CrossRef] [PubMed]
  46. Tanaka, T.; Narazaki, M.; Kishimoto, T. IL-6 in Inflammation, Immunity, and Disease. Cold Spring Harb. Perspect. Biol. 2014, 6, a016295. [Google Scholar] [CrossRef]
  47. Wright, J.R. Immunoregulatory functions of surfactant proteins. Nat. Rev. Immunol. 2005, 5, 58–68. [Google Scholar] [CrossRef]
  48. Woof, J.M.; Mestecky, J. Mucosal immunoglobulins. Immunol. Rev. 2005, 206, 64–82. [Google Scholar] [CrossRef]
  49. Dickson, R.P.; Erb-Downward, J.R.; Freeman, C.M.; McCloskey, L.; Beck, J.M.; Huffnagle, G.B.; Curtis, J.L. Spatial Variation in the Healthy Human Lung Microbiome and the Adapted Island Model of Lung Biogeography. Ann. Am. Thorac. Soc. 2015, 12, 821–830. [Google Scholar] [CrossRef]
  50. Stroman, D.W.; Mintun, K.; Epstein, A.B.; Brimer, C.M.; Patel, C.R.; Branch, J.D.; Najafi-Tagol, K. Reduction in bacterial load using hypochlorous acid hygiene solution on ocular skin. Clin. Ophthalmol. 2017, 11, 707–714. [Google Scholar] [CrossRef]
  51. Hong, I.; Lee, H.G.; Keum, H.L.; Kim, M.J.; Jung, U.W.; Kim, K.; Kim, S.Y.; Park, T.; Kim, H.J.; Kim, J.J.; et al. Clinical and microbiological efficacy of pyrophosphate containing toothpaste: A double-blinded placebo-controlled randomized clinical trial. Microorganisms 2020, 8, 1806. [Google Scholar] [CrossRef]
  52. Zayed, N.; Vertommen, R.; Simoens, K.; Bernaerts, K.; Boon, N.; Srivastava, M.G.; Braem, A.; Van Holm, W.; Castro, A.B.; Teughels, W. How well do antimicrobial mouth rinses prevent dysbiosis in an in vitro periodontitis biofilm model? J. Periodontol. 2024, 95, 880–891. [Google Scholar] [CrossRef] [PubMed]
  53. U.S. Food & Drug Administration. 510(k) Premarket Notification—Spectricept Skin and Wound Cleanser (K213514). 2023. Available online: https://www.accessdata.fda.gov/cdrh_docs/pdf21/K213514.pdf (accessed on 3 July 2025).
  54. U.S. Food & Drug Administration. 510(k) Premarket Notification—Microdacyn Wound Care Solution (K233399). 2024. Available online: https://www.accessdata.fda.gov/cdrh_docs/pdf23/K233399.pdf (accessed on 2 July 2025).
  55. Del Rosso, J.Q.; Bhatia, N. Status Report on Topical Hypochlorous Acid: Clinical Relevance of Specific Formulations, Potential Modes of Action, and Study Outcomes. J. Clin. Aesthetic Dermatol. 2018, 11, 36–39. Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303114/ (accessed on 14 June 2025).
  56. Menta, N.; Vidal, S.I.; Friedman, A. Hypochlorous Acid: A Blast from the Past. J. Drugs Dermatol. 2024, 23, 909–910. Available online: https://jddonline.com/articles/hypochlorous-acid-blast-past-S1545961624P1024X/ (accessed on 1 September 2025).
  57. Regeno GmbH. Patient Information Leaflet “Plasma Liquid Nasal Spray Gel.”; Regeno, GmbH: Mannheim, Germany, 2022. [Google Scholar]
  58. Severing, A.L.; Rembe, J.D.; Koester, V.; Stuermer, E.K. Safety and efficacy profiles of different commercial sodium hypochlorite/hypochlorous acid solutions (NaClO/HClO): Antimicrobial efficacy, cytotoxic impact and physicochemical parameters in vitro. J. Antimicrob. Chemother. 2019, 74, 365–372. [Google Scholar] [CrossRef]
  59. TRGS 900; Arbeitsplatzgrenzwerte. Ausschuss für Gefahrstoffe (AGS): Dortmund, Germany, 2024.
  60. Actimaris, A.G. Patient Information Leaflet “Actimaris Nasal Spray.”; Actimaris, A.G.: Appenzell, Switzerland, 2020. [Google Scholar]
  61. Sismanoglu, S.; Ercal, P. The cytotoxic effects of various endodontic irrigants on the viability of dental mesenchymal stem cells. Aust. Endod. J. 2022, 48, 305–312. [Google Scholar] [CrossRef]
  62. Mehendale, F.V.; Clayton, G.; Homyer, K.M.; Reynolds, D.M. HOCl vs OCl−: Clarification on chlorine-based disinfectants used within clinical settings. J. Glob. Health Rep. 2023, 7, e2023052. [Google Scholar] [CrossRef]
  63. Benedusi, M.; Tamburini, E.; Sicurella, M.; Summa, D.; Ferrara, F.; Marconi, P.; Cervellati, F.; Costa, S.; Valacchi, G. The Lesson Learned from the COVID-19 Pandemic: Can an Active Chemical Be Effective, Safe, Harmless-for-Humans and Low-Cost at a Time? Evidence on Aerosolized Hypochlorous Acid. Int. J. Environ. Res. Public Health 2022, 19, 13163. [Google Scholar] [CrossRef]
  64. Lewandowski, R.B.; Stȩpińska, M.; Osuchowski, Ł.; Kasprzycka, W.; Dobrzyńska, M.; Mierczyk, Z.; Trafny, E.A. The HOCl dry fog-is it safe for human cells? PLoS ONE 2024, 19, e0304602. [Google Scholar] [CrossRef]
  65. Boecker, D.; Breves, R.; Zhang, Z.; Bulitta, C. Antimicrobial Activity in the Gasphase with Hypochloric Acid. Curr. Dir. Biomed. Eng. 2021, 7, 511–514. [Google Scholar] [CrossRef]
  66. Rasmussen, E.D.; Robins, L.I.; Stone, J.R.; Williams, J.F. Inhalation of Microaerosolized Hypochlorous Acid (HOCl): Biochemical, Antimicrobial, and Pathological Assessment. Arch. Intern. Med. Res. 2022, 05, 311–318. [Google Scholar] [CrossRef]
  67. Noszticzius, Z.; Wittmann, M.; Kály-Kullai, K.; Beregvári, Z.; Kiss, I.; Rosivall, L.; Szegedi, J. Chlorine dioxide is a size-selective antimicrobial agent. PLoS ONE 2013, 8, e79157. [Google Scholar] [CrossRef]
  68. Leiby, K.L.; Raredon, M.S.B.; Niklason, L.E. Bioengineering the blood-gas barrier. Compr. Physiol. 2020, 10, 415–452. [Google Scholar] [CrossRef] [PubMed]
  69. Qadir Tantry, I.; Ali, A.; Mahmood, R. Hypochlorous acid decreases antioxidant power, inhibits plasma membrane redox system and pathways of glucose metabolism in human red blood cells. Toxicol Res. 2021, 10, 264–271. [Google Scholar] [CrossRef]
  70. Jin, S.J.; Piao, S.; Cha, Y.N.; Kim, C. Taurine chloramine activates Nrf2, increases HO-1 expression and protects cells from death caused by hydrogen peroxide. J. Clin. Biochem. Nutr. 2009, 45, 37–43. [Google Scholar] [CrossRef]
  71. Kearns, S.; Dawson, R. Cytoprotective Effect of Taurine Against Hypochlorous Acid Toxicity to PC12 Cells. In Taurine 4; Advances in Experimental Medicine and Biology; Della Corte, L., Huxtable, R., Sgaragli, G., Tipton, K., Eds.; Springer: Berlin/Heidelberg, Germany, 2002; Volume 483, pp. 563–570. [Google Scholar] [CrossRef]
  72. Antosova, M.; Mokra, D.; Pepucha, L.; Plevkova, J.; Buday, T.; Sterusky, M.; Bencova, A. Physiology of nitric oxide in the respiratory system. Physiol. Res. Czech Acad. Sci. 2017, 66, S159–S172. [Google Scholar] [CrossRef] [PubMed]
  73. Storkey, C.; Davies, M.J.; Pattison, D.I. Reevaluation of the rate constants for the reaction of hypochlorous acid (HOCl) with cysteine, methionine, and peptide derivatives using a new competition kinetic approach. Free Radic. Biol. Med. 2014, 73, 60–66. [Google Scholar] [CrossRef] [PubMed]
  74. Ashby, M.T.; Carlson, A.C.; Scott, M.J. Redox Buffering of Hypochlorous Acid by Thiocyanate in Physiologic Fluids. J. Am. Chem. Soc. 2004, 126, 15976–15977. [Google Scholar] [CrossRef]
  75. Cegolon, L.; Mirandola, M.; Salaris, C.; Salvati, M.V.; Mastrangelo, G.; Salata, C. Hypothiocyanite and Hypothiocyanite/Lactoferrin Mixture Exhibit Virucidal Activity In Vitro against SARS-CoV-2. Pathogens 2021, 10, 233. [Google Scholar] [CrossRef]
  76. Bárcena, C.; Mayoral, P.; Quirós, P.M. Mitohormesis, an Antiaging Paradigm. Int. Rev. Cell. Mol. Biol. 2018, 340, 35–77. [Google Scholar] [CrossRef]
  77. Merry, T.L.; Ristow, M. Mitohormesis in exercise training. Free Radic. Biol. Med. 2016, 98, 123–130. [Google Scholar] [CrossRef]
  78. McDonnell, G.; Russell, A.D. Antiseptics and Disinfectants: Activity, Action, and Resistance. Clin. Microbiol. Rev. 1999, 12, 147–179. [Google Scholar] [CrossRef] [PubMed]
  79. McKenna, S.M.; Davies, K.J.A. The inhibition of bacterial growth by hypochlorous acid. Possible role in the bactericidal activity of phagocytes. Biochem. J. 1988, 254, 685–692. [Google Scholar] [CrossRef]
  80. Nadhan, R.; Patra, D.; Krishnan, N.; Rajan, A.; Gopala, S.; Ravi, D.; Srinivas, P. Perspectives on mechanistic implications of ROS inducers for targeting viral infections. Eur. J. Pharmacol. 2021, 890, 173621. [Google Scholar] [CrossRef]
  81. Kayesh, M.E.H.; Kohara, M.; Tsukiyama-Kohara, K. Effects of oxidative stress on viral infections: An overview. npj Viruses 2025, 3, 27. [Google Scholar] [CrossRef] [PubMed]
  82. Hati, S.; Bhattacharyya, S. Impact of Thiol-Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin-Converting Enzyme 2 Receptor. ACS Omega 2020, 5, 16292–16298. [Google Scholar] [CrossRef]
  83. Karimi, M.; Crossett, B.; Cordwell, S.J.; Pattison, D.I.; Davies, M.J. Characterization of disulfide (cystine) oxidation by HOCl in a model peptide: Evidence for oxygen addition, disulfide bond cleavage and adduct formation with thiols. Free Radic. Biol. Med. 2020, 154, 62–74. [Google Scholar] [CrossRef]
  84. Landino, L.M.; Lessard, E.E. Lactate Dehydrogenase-B Oxidation and Inhibition by Singlet Oxygen and Hypochlorous Acid. Oxygen 2024, 4, 432–448. [Google Scholar] [CrossRef]
  85. Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020, 581, 215–220. [Google Scholar] [CrossRef] [PubMed]
  86. Schrödinger, L.L.C. The PyMOL Molecular Graphics System. 2024. Available online: https://pymol.org (accessed on 23 June 2025).
  87. Debnath, U.; Mitra, A.; Dewaker, V.; Prabhakar, Y.S.; Tadala, R.; Krishnan, K.; Wagh, P.; Velusamy, U.; Baliyan, A.; Kurpad, A.V.; et al. Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine: An exploration of probable mechanism of action to combat COVID-19. J. Biomol. Struct. Dyn. 2024, 42, 5042–5052. [Google Scholar] [CrossRef]
  88. Andrés, C.M.C.; Pérez de la Lastra, J.M.; Andrés Juan, C.; Plou, F.J.; Pérez-Lebeña, E. Impact of Reactive Species on Amino Acids—Biological Relevance in Proteins and Induced Pathologies. Int. J. Mol. Sci. 2022, 23, 14049. [Google Scholar] [CrossRef]
  89. Hicks, S.N.; Chaiwatpongsakorn, S.; Costello, H.M.; McLellan, J.S.; Ray, W.; Peeples, M.E. Five Residues in the Apical Loop of the Respiratory Syncytial Virus Fusion Protein F2 Subunit Are Critical for Its Fusion Activity. J. Virol. 2018, 92, e00621-18. [Google Scholar] [CrossRef]
  90. McLellan, J.S.; Yang, Y.; Graham, B.S.; Kwong, P.D. Structure of Respiratory Syncytial Virus Fusion Glycoprotein in the Postfusion Conformation Reveals Preservation of Neutralizing Epitopes. J. Virol. 2011, 85, 7788–7796. [Google Scholar] [CrossRef] [PubMed]
  91. McLellan, J.S.; Chen, M.; Leung, S.; Graepel, K.W.; Du, X.; Yang, Y.; Zhou, T.; Baxa, U.; Yasuda, E.; Beaumont, T.; et al. Crystal Structure of Respiratory Syncytial Virus Fusion Glycoprotein Stabilized in the Prefusion Conformation by Human Antibody D25. Science 2013, 340, 1113–1117. [Google Scholar] [CrossRef] [PubMed]
  92. Florido, M.; Chiu, J.; Hogg, P.J. Influenza A Virus Hemagglutinin Is Produced in Different Disulfide-Bonded States. Antioxid. Redox Signal. 2021, 35, 1081–1092. [Google Scholar] [CrossRef] [PubMed]
  93. Yang, S.; Chuang, C.Y.; Huang, H.C.; Fang, W. Inactivation of Avian Influenza Virus Aerosol Using Membrane-Less Electrolyzed Water Spraying. Aerobiology 2023, 1, 70–81. [Google Scholar] [CrossRef]
  94. Urushidani, M.; Kawayoshi, A.; Kotaki, T.; Saeki, K.; Mori, Y.; Kameoka, M. Inactivation of SARS-CoV-2 and influenza A virus by dry fogging hypochlorous acid solution and hydrogen peroxide solution. PLoS ONE 2022, 17, e0261802. [Google Scholar] [CrossRef] [PubMed]
  95. Zhao, Y.; Xin, H.; Zhao, D.; Zheng, W.; Tian, W.; Ma, H.; Liu, K.; Hu, H.; Wang, T.; Soupir, M. Free chlorine loss during spraying of membraneless acidic electrolyzed water and its antimicrobial effect on airborne bacteria from poultry house. Ann. Agric. Environ. Med. 2014, 21, 249–255. [Google Scholar] [CrossRef]
  96. Amatore, D.; Sgarbanti, R.; Aquilano, K.; Baldelli, S.; Limongi, D.; Civitelli, L.; Nencioni, L.; Garaci, E.; Ciriolo, M.R.; Palamara, A.T. Influenza virus replication in lung epithelial cells depends on redox-sensitive pathways activated by NOX4-derived ROS. Cell. Microbiol. 2015, 17, 131–145. [Google Scholar] [CrossRef]
  97. Venkitanarayanan, K.S.; Ezeike, G.O.I.; Hung, Y.C.; Doyle, M.P. Inactivation of Escherichia coli O157:H7 and Listeria monocytogenes on Plastic Kitchen Cutting Boards by Electrolyzed Oxidizing Water. J. Food Prot. 1999, 62, 857–860. [Google Scholar] [CrossRef]
  98. Kubota, A.; Goda, T.; Tsuru, T.; Yonekura, T.; Yagi, M.; Kawahara, H.; Yoneda, A.; Tazuke, Y.; Tani, G.; Ishii, T.; et al. Efficacy and safety of strong acid electrolyzed water for peritoneal lavage to prevent surgical site infection in patients with perforated appendicitis. Surg. Today 2015, 45, 876–879. [Google Scholar] [CrossRef]
  99. Fernández, L.G.; Matthews, M.R.; Seal, L. Intraabdominal Lavage of Hypochlorous Acid: A New Paradigm for the Septic and Open Abdomen. Wounds 2020, 32, 107–114. [Google Scholar]
  100. Kampf, G. Antibiotic Resistance Can Be Enhanced in Gram-Positive Species by Some Biocidal Agents Used for Disinfection. Antibiotics 2019, 8, 13. [Google Scholar] [CrossRef]
  101. Li, K.; Deng, Z.; Lei, C.; Ding, X.; Li, J.; Wang, C. The Role of Oxidative Stress in Tumorigenesis and Progression. Cells 2024, 13, 441. [Google Scholar] [CrossRef]
  102. Gorrini, C.; Harris, I.S.; Mak, T.W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 2013, 12, 931–947. [Google Scholar] [CrossRef]
  103. Bauer, G. HOCl and the control of oncogenesis. J. Inorg. Biochem. 2018, 179, 10–23. [Google Scholar] [CrossRef] [PubMed]
  104. Leung, T.H.; Zhang, L.F.; Wang, J.; Ning, S.; Knox, S.J.; Kim, S.K. Topical hypochlorite ameliorates NF-κB-mediated skin diseases in mice. J. Clin. Investig. 2013, 123, 5361–5370. [Google Scholar] [CrossRef]
  105. Natarelli, N.; Nong, Y.; Maloh, J.; Sivamani, R. Hypochlorous Acid: Applications in Dermatology. J. Integr. Dermatol. Available online: https://jintegrativederm.org/article/view/93/17 (accessed on 23 February 2025).
  106. Jandova, J.; Snell, J.; Hua, A.; Dickinson, S.; Fimbres, J.; Wondrak, G.T. Topical hypochlorous acid (HOCl) blocks inflammatory gene expression and tumorigenic progression in UV-exposed SKH-1 high risk mouse skin. Redox Biol. 2021, 45, 102042. [Google Scholar] [CrossRef]
  107. Snell, J.A.; Jandova, J.; Wondrak, G.T. Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer. Front. Oncol. 2022, 12, 887220. [Google Scholar] [CrossRef] [PubMed]
  108. Zwicker, P.; Freitag, M.; Heidel, F.H.; Kocher, T.; Kramer, A. Antiseptic efficacy of two mouth rinses in the oral cavity to identify a suitable rinsing solution in radiation- or chemotherapy induced mucositis. BMC Oral Health 2023, 23, 176. [Google Scholar] [CrossRef]
  109. Robins, L.I.; Keim, E.K.; Robins, D.B.; Edgar, J.S.; Meschke, J.S.; Gafken, P.R.; Williams, J.F. Modifications of IL-6 by Hypochlorous Acids: Effects on Receptor Binding. ACS Omega 2021, 6, 35593–35599. [Google Scholar] [CrossRef] [PubMed]
  110. Marcinkiewicz, J.; Grabowska, A.; Bereta, J.; Stelmaszynska, T. Taurine chloramine, a product of activated neutrophils, inhibits in vitro the generation of nitric oxide and other macrophage inflammatory mediators. J. Leukoc. Biol. 1995, 58, 667–674. [Google Scholar] [CrossRef]
  111. Mueller, C.A.; Winter, M.; Renner, B. A Concept for the Reduction of Mucosal SARS-CoV-2 Load using Hypochloric Acid Solutions. Drug Res. 2021, 71, 348–350. [Google Scholar] [CrossRef]
  112. Mueller, C.A.; Winter, M.; Lippert, A.; Hochauf-Stange, K.; Renner, B. Double-Blind, Randomised, Placebo-Controlled Study to Investigate the Efficacy of Nasal Spray and Mouth Wash Containing Hypochlorous Acid in SARS-CoV-2 Infected Patients; Deutsches Register Klinischer Studien (DRKS). 2022. Available online: https://drks.de/search/de/trial/DRKS00030721 (accessed on 24 April 2024).
  113. The Committee on Efficacy Assessment of Disinfecting Substances Alternative to Alcohol for Use Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Final Report on Efficacy Assessment of Disinfecting Substances Alternative to Alcohol for Use Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). 2020. Available online: https://www.nite.go.jp/data/000115863.pdf (accessed on 2 July 2025).
  114. Park, G.W.; Boston, D.M.; Kase, J.A.; Sampson, M.N.; Sobsey, M.D. Evaluation of liquid- and fog-based application of sterilox hypochlorous acid solution for surface inactivation of human norovirus. Appl. Environ. Microbiol. 2007, 73, 4463–4468. [Google Scholar] [CrossRef]
  115. Aherne, O.; Ortiz, R.; Fazli, M.M.; Davies, J.R. Effects of stabilized hypochlorous acid on oral biofilm bacteria. BMC Oral Health 2022, 22, 415. [Google Scholar] [CrossRef]
  116. Nizer WSda, C.; Inkovskiy, V.; Overhage, J. Surviving reactive chlorine stress: Responses of gram-negative bacteria to hypochlorous acid. Microorganisms 2020, 8, 1220. [Google Scholar] [CrossRef]
  117. Posch, W.; Vosper, J.; Noureen, A.; Zaderer, V.; Witting, C.; Bertacchi, G.; Gstir, R.; Filipek, P.A.; Bonn, G.K.; Huber, L.A.; et al. C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia. J. Allergy Clin. Immunol. 2021, 147, 2083–2097.e6. [Google Scholar] [CrossRef]
  118. Lafon, E.; Diem, G.; Witting, C.; Zaderer, V.; Bellmann-Weiler, R.M.; Reindl, M.; Bauer, A.; Griesmacher, A.; Fux, V.; Hoermann, G.; et al. Potent SARS-CoV-2-Specific T Cell Immunity and Low Anaphylatoxin Levels Correlate with Mild Disease Progression in COVID-19 Patients. Front. Immunol. 2021, 12, 684014. [Google Scholar] [CrossRef] [PubMed]
  119. Held, A.M.; Halko, D.J.; Hurst, J.K. Mechanisms of chlorine oxidation of hydrogen peroxide. J. Am. Chem. Soc. 1978, 100, 5732–5740. [Google Scholar] [CrossRef]
  120. Hakim, H.; Thammakarn, C.; Suguro, A.; Ishida, Y.; Kawamura, A.; Tamura, M.; Satoh, K.; Tsujimura, M.; Hasegawa, T.; Takehara, K. Evaluation of sprayed hypochlorous acid solutions for their virucidal activity against avian influenza virus through in vitro experiments. J. Vet. Med. Sci. 2015, 77, 211–215. [Google Scholar] [CrossRef]
  121. Yu, M.S.; Park, H.W.; Kwon, H.J.; Jang, Y.J. The Effect of a Low Concentration of Hypochlorous Acid on Rhinovirus Infection of Nasal Epithelial Cells. Am. J. Rhinol. Allergy 2011, 25, 40–44. [Google Scholar] [CrossRef]
  122. Guan, H.; Nuth, M.; Weiss, S.R.; Fausto, A.; Liu, Y.; Koo, H.; Wolff, M.S.; Ricciardi, R.P. HOCl Rapidly Kills Corona, Flu, and Herpes to Prevent Aerosol Spread. J. Dent. Res. 2023, 102, 1031–1037. [Google Scholar] [CrossRef]
  123. Darie, A.M.; Khanna, N.; Jahn, K.; Osthoff, M.; Bassetti, S.; Osthoff, M.; Schumann, D.M.; Albrich, W.C.; Hirsch, H.; Brutsche, M.; et al. Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in hospitalised patients with pneumonia at risk of Gram-negative bacterial infection (Flagship II): A multicentre, randomised controlled trial. Lancet Respir. Med. 2022, 10, 877–887. [Google Scholar] [CrossRef] [PubMed]
Viruses 17 01219 g001
Figure 1. SARS-CoV-2 receptor-binding domain bound to the extracellular domain of the human ACE2-receptor. The receptor-binding domain (RBD) of the spike protein (green) is engaging human ACE2 (cyan) through the receptor-binding motif (RBM, yellow). The cysteine residues C480 and C488 (red), as well as their disulfide bridge, are sterically exposed and critical for ACE2 binding. Structure visualized using PyMOL [86] and based on PDB entry 6M0J [85].
Figure 1. SARS-CoV-2 receptor-binding domain bound to the extracellular domain of the human ACE2-receptor. The receptor-binding domain (RBD) of the spike protein (green) is engaging human ACE2 (cyan) through the receptor-binding motif (RBM, yellow). The cysteine residues C480 and C488 (red), as well as their disulfide bridge, are sterically exposed and critical for ACE2 binding. Structure visualized using PyMOL [86] and based on PDB entry 6M0J [85].
Viruses 17 01219 g001
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Winter, M.; Boecker, D.; Posch, W. Hypochlorous Acid (HOCl) as a Promising Respiratory Antiseptic. Viruses 2025, 17, 1219. https://doi.org/10.3390/v17091219

AMA Style

Winter M, Boecker D, Posch W. Hypochlorous Acid (HOCl) as a Promising Respiratory Antiseptic. Viruses. 2025; 17(9):1219. https://doi.org/10.3390/v17091219

Chicago/Turabian Style

Winter, Michael, Dirk Boecker, and Wilfried Posch. 2025. "Hypochlorous Acid (HOCl) as a Promising Respiratory Antiseptic" Viruses 17, no. 9: 1219. https://doi.org/10.3390/v17091219

APA Style

Winter, M., Boecker, D., & Posch, W. (2025). Hypochlorous Acid (HOCl) as a Promising Respiratory Antiseptic. Viruses, 17(9), 1219. https://doi.org/10.3390/v17091219

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop