Review

Immunological and toxicological effects of bad indoor air to cause Dampness and Mold Hypersensitivity Syndrome

  • Water damage in buildings is a universe problem. Long-lasting or cumulative stay in water damaged buildings is a serious health hazard. Exposure to fungal and bacterial toxins, nanoparticles from dampness microbiota as well as decay products from construction materials together with biocides used for cleaning will first cause irritation of the mucosa and later chronic inflammation with stimulation or inhibition of the compartments of the innate and/or adaptive immunity. Mold-related disease has been called Dampness and Mold Hypersensitive Syndrome (DMHS) because hypersensitivity is the cornerstone feature of the disease. The background of hypersensitivity is both immunologic processes and hyperactivation of sensory receptors, neurogenic inflammation and central sensitisation. Immunologic hypersensitivity can occur either through the production of mold specific IgE-class antibodies, which is rare, or through sensitisation and proliferation of T and B specific lymphocyte clones. Immunological switch to Th2/Th17 arm of adaptive immunity often occurs. DMHS is a systemic and multi-organ disease where involvement of mucosa of pulmonary or gastrointestinal tract is central to the pathology. Symptoms include recurrent infections, chronic rhinosinusitis, swelling of the sinuses, irritation of the eyes and skin, voice problems, chronic non-productive cough, neurological symptoms, joint and muscle symptoms, irritable bowel syndrome and cognitive problems. Underdiagnosed or neglected continuous insidious inflammation may lead to Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) especially when trigged by new infections or even vaccination. Multiple Chemical Sensitivity (MCS) may also develop, however in the later stages of the disease. Chronic cough is sometimes diagnosed as asthma if the criteria for asthma are met. Non-productive cough may also manifest allergic alveolitis, which is often overlooked. Avoidance of new exposure to dampness microbiota is crucial for recovery. We review the underlying toxicological and immunological mechanisms that are central in the pathology of DMHS.

    Citation: Tamara Tuuminen, Jouni Lohi. Immunological and toxicological effects of bad indoor air to cause Dampness and Mold Hypersensitivity Syndrome[J]. AIMS Allergy and Immunology, 2018, 2(4): 190-204. doi: 10.3934/Allergy.2018.4.190

    Related Papers:

    [1] Xiujuan Li, Jianmin Lin, Yan Li, Min Zhu, Minchuan Lin, Chenxi Li . Inhalation allergen sensitization patterns in children with allergic rhinitis and asthma. AIMS Allergy and Immunology, 2024, 8(4): 254-264. doi: 10.3934/Allergy.2024015
    [2] Kremena Naydenova, Tsvetelina Velikova, Vasil Dimitrov . Interactions of allergic rhinitis and bronchial asthma at mucosal immunology level. AIMS Allergy and Immunology, 2019, 3(1): 1-12. doi: 10.3934/Allergy.2019.1.1
    [3] Haiyan Guo, Mingsheng Lei, Jinan Ma, Hongchun Du, Youming Zhang . Allergy and ferroptosis. AIMS Allergy and Immunology, 2025, 9(1): 8-26. doi: 10.3934/Allergy.2025002
    [4] Sammi Wong, Sara Hasan, Christina Parducci, Bernadette Ann Riley . The gastrointestinal effects amongst Ehlers-Danlos syndrome, mast cell activation syndrome and postural orthostatic tachycardia syndrome. AIMS Allergy and Immunology, 2022, 6(2): 19-24. doi: 10.3934/Allergy.2022004
    [5] Bono Eleonora, Zucca Federica, Ortolani Valeria Giuseppina Rita, Caron Lea, Eplite Angelo, Carsana Luca, Iemoli Enrico . Non-allergic rhinitis with eosinophilia syndrome treated with mepolizumab: A case report. AIMS Allergy and Immunology, 2023, 7(3): 176-182. doi: 10.3934/Allergy.2023012
    [6] Gianna Moscato, Gianni Pala . Occupational allergy to food-derived allergens. AIMS Allergy and Immunology, 2017, 1(1): 21-30. doi: 10.3934/Allergy.2017.1.21
    [7] Moufag Mohammed Saeed Tayeb . Role of IgG food test in patients with allergic diseases. AIMS Allergy and Immunology, 2023, 7(2): 154-163. doi: 10.3934/Allergy.2023010
    [8] Moufag Mohammed Saeed Tayeb . The relationship between mold sensitization and allergic diseases: a retrospective study (Jeddah, Saudi). AIMS Allergy and Immunology, 2020, 4(1): 14-19. doi: 10.3934/Allergy.2020002
    [9] Norio Kodaka, Chihiro Nakano, Takeshi Oshio, Hiroto Matsuse . The treatment of severe uncontrolled asthma using biologics. AIMS Allergy and Immunology, 2020, 4(1): 1-13. doi: 10.3934/Allergy.2020001
    [10] Amolak S Bansal, Alex Nicholas, Nazira Sumar, Veronica Varney . Mast cells, mediators, and symptomatic activation. AIMS Allergy and Immunology, 2024, 8(1): 34-55. doi: 10.3934/Allergy.2024004
  • Water damage in buildings is a universe problem. Long-lasting or cumulative stay in water damaged buildings is a serious health hazard. Exposure to fungal and bacterial toxins, nanoparticles from dampness microbiota as well as decay products from construction materials together with biocides used for cleaning will first cause irritation of the mucosa and later chronic inflammation with stimulation or inhibition of the compartments of the innate and/or adaptive immunity. Mold-related disease has been called Dampness and Mold Hypersensitive Syndrome (DMHS) because hypersensitivity is the cornerstone feature of the disease. The background of hypersensitivity is both immunologic processes and hyperactivation of sensory receptors, neurogenic inflammation and central sensitisation. Immunologic hypersensitivity can occur either through the production of mold specific IgE-class antibodies, which is rare, or through sensitisation and proliferation of T and B specific lymphocyte clones. Immunological switch to Th2/Th17 arm of adaptive immunity often occurs. DMHS is a systemic and multi-organ disease where involvement of mucosa of pulmonary or gastrointestinal tract is central to the pathology. Symptoms include recurrent infections, chronic rhinosinusitis, swelling of the sinuses, irritation of the eyes and skin, voice problems, chronic non-productive cough, neurological symptoms, joint and muscle symptoms, irritable bowel syndrome and cognitive problems. Underdiagnosed or neglected continuous insidious inflammation may lead to Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) especially when trigged by new infections or even vaccination. Multiple Chemical Sensitivity (MCS) may also develop, however in the later stages of the disease. Chronic cough is sometimes diagnosed as asthma if the criteria for asthma are met. Non-productive cough may also manifest allergic alveolitis, which is often overlooked. Avoidance of new exposure to dampness microbiota is crucial for recovery. We review the underlying toxicological and immunological mechanisms that are central in the pathology of DMHS.


    1. Introduction

    Current membrane technologies are important in many industrial separation processes, especially in water purification and desalination. However, the large operating pressure gradient that is required for conventional reverse osmosis filtration makes water purification a very expensive process [1,2,3,4]. The discovery of aquaporin proteins has provided us with a revolutionary alternative to current membranes used in water purification.

    Aquaporins (Aqp) are transmembrane proteins that are present in the biological membranes of organisms such as plants, mammals and bacteria [5,6]. They form pores that act as water channels, which play key roles in selectively allowing only water molecules to move across the plasma membrane while rejecting protons, charged particles and other solutes [7,8]. Aquaporin Z (AqpZ) is of special interest in water purification and seawater desalination. This is because AqpZhas been successfully expressed in Escherichia coli as reported by Soupene et al. [9], and has been purified in high concentrations to be used for integration into biomimetic membranes for water filtration [10,11]. Furthermore, AqpZ is the smallest, simplest and most robust aquaporin in the Aqp family and it can retain its properties after reconstitution in polymeric bilayer membrane vesicles [12].

    Similar to other aquaporins, AqpZ naturally exists as a tetramer made up of 4 equal sub-units (or monomers) [13], with each aquaporin monomer having six transmembrane α-helical structuresand five connecting loops named A to E [12]. Each aquaporin monomer contains an individual pore, or water channel, that allows the transport of water bi-directionally withwater transport rates of up to 109 molecules per second. Loops B and E contain the most highly conserved residues, including the asparagine-proline-alanine (NPA) signature motif of Aqp, which are directly involved in the water channel function of Aqp. Loops B and E fold into the membrane from opposite sides of the bilayer, overlapping midway through the bilayer where they are surrounded by six transmembrane helices, forming the “hour-glass” model of the water channel. Owing to its unique hour-glass configuration with the NPA motif, AqpZ iscapable of achieving high water selectivity and 100% salt rejection. Three features of the water channel contribute to this high selectivity for water, which are size restriction, electrostatic repulsion and water dipole re-orientation [13]. Firstly, the narrowest constriction of the pore has a diameter of 2.8 Å [13], which is approximately the diameter of a water molecule. Hence, water molecules are physically sieved through and allowed to penetrate while other ions and solutes are rejected due to this selective property. Another feature contributing to the high water selectivity of aquaporin is the electrostatic repulsion induced by one of the conserved residue, Arg-195, located at the narrowest pore constriction [13,14,15,16]. This residue carries a strong positive charge which repels cations including protonated water, H3O+, hence preventing the passage of positively-charged ions. The third feature is that the hemipore loops carrying the NPA motifs—Loops B and E—form helices that meet midway of the channel, producing positively charged dipoles that reorient water molecules. This water dipole reorientation results in the opposite alignment of water molecules, which disrupts hydrogen bonding between neighbouring water molecules. Hence, the conductance of H+ ions is eliminated [17].

    In most Aqp, the hydrophobic channels function as open channels, but some plant aquaporins, such as the spinach Aqp, have been described by Chaumont et al. (2005) to exhibit a form of gating mechanism. These Aqp are able to close up their channels under extreme conditions in order to stop water exchange altogether, which lends credence to the basis that AqpZ permeability is likely to vary with external conditions, eventhough they may or may not exhibit the same form of gating mechanisms observed [18]. However, the water filtration mechanisms by which these Aqp function are not fully understood. The protein will be influenced by external factors such as pH and temperature, which can cause a disruption to its structure and affect the protein’s functionality and properties [19]. The different external conditions can induce structural changes of the Aqp proteins and may lead to an adverse or favorable effect on the water transport and selection mechanism. Hence, it may result in a change to the osmotic permeability of AqpZ.

    In addition, the thickness of the phospholipid bilayer may regulate transmembrane proteins funcationalities due to the hydrophobic mismatch between the hydrophobic length of the transmembrane proteins and the hydrophobic thickness of the bilayers [20,21,22,23,24,25,26]. To counteract the hydrophobic mismatch, either the surrounding bilayer thickness or the protein conformation will change, for example resulting in an activity change of melibiose tranporters or mechanosensitive ion channels [20,21,22,23,24,25,26]. To date, it remains unclear how the osmotic permeability of AqpZ will be affected by the hydrophobic thickness of the surrounding bialyer membrane.

    Compared to phospholipids, amphiphilic block copolymers are more suitable in the fabrication of AqpZ reconstituted biomimetic membranes for the purpose of water filtration because block copolymers possess higher chemical and mechanical stability due to their chemical structures and flexible functional designs. ABA block copolymer, such as poly(2-methyloxazoline)-b-poly(dimethylsiloxane)-b-poly(2-methyloxazoline) (PMOXA-PDMS-PMOXA), has been widely used in fabrication of AqpZ-based biomimetic membrane for water purification [1,27,28,29,30,31]. It has been reported that the permeability of an AqpZ-reconstitutedPMOXA-PDMS-PMOXA membrane is 167 mm/s/bar, which is by two orders of magnitude greater than commercial polymeric membranes [1]. Therefore, we chose the amphiphilic block copolymer of PMOXA-PDMS-PMOXAs as the bilayer matrix for AqpZ reconstitution in this work.

    The rationale of the present study is to gain further insight into the regulation of AqpZ permeability through environmental conditions, including the protein-bilayer hydrophobic mismatch, pH and temperature. We reconstituted AqpZ into vesicles that are made from a series of amphiphilic block copolymers of PMOXA-PDMS-PMOXA with various hydrophobic molecular weights. The osmotic permeability of AqpZ in these vesicles is determined by stopped-flow spectroscopy. In addition, the temperature and pH of the vesicle solutions were adjusted within wide ranges to investigate the regulation of osmotic permeability of the AqpZ at different external conditions.

    2. Materials and Methods

    2.1. Expression and purification of Aquaporin Z

    Aquaporin Z has been prepared as reported by Calamita et al. [6] and in our previous studies [27,28,29,30,31]. Briefly, E. coli genomic DNA was extracted and the aqpZ gene was amplified and cloned into the pCR-4 vector using the TOPO cloning kit (Invitrogen, USA). The positive clones were sequenced and further subcloned into a modified expression vector, the pQE-30 Xa expression vector, with ampicillin selection and an amino-terminal 10x His-affinity tag (Qiagen, USA). The E. coli strain TOP10F was transformed and grown to 0.6-1OD at 600 nm in LB with 100 mg/l of ampicillin and subsequently induced with 1 mM of isopropyl-D-thiogalactoside. The harvested cells were resuspended in one 1/50 culture volume of ice-cold lysis buffer containing 100 mM of K2HPO4, 1 mM of MgSO4, 1 mM of phenylmethylsulfonylfluoride (PMSF), and 0.1 mg/ml of deoxyribonuclease I (pH 7.0). Cells were subjected to 4 lysis cycles in a French press (115 × 106 Pa at 4 °C). The unbroken cells and debris were separated from the cell lysate by centrifugation at 10, 000 g and discarded. Membrane fractions were recovered from the supernatant by centrifugation at 100, 000 g. AqpZ was solubilized from pellets by agitation in 1% dodecyl maltoside and PBS [12]. The solubilized protein was purified through Ni-NTA resin (Qiagen, USA), washed, and eluted with PBS (pH 7.4) and 250 mM of imidazole. The imidazole was removed using a Bio-Rad (Hercules, California, United States) Econo-Pac DG10 desalting column [32]. The resulting recombinant Aquaporin Z protein contained the 10 His-tag at the protein’s N-terminus and was utilized for embedding into membranes and vesicles.

    2.2. ABA triblock copolymers

    A series of ABA triblock copolymers, poly(2-methyloxazoline)-block-poly(dimethylsiloxane)-block-poly(2-methyloxazoline) (PMOXA-PDMS-PMOXA, Polymer Source Inc.), with various hydrophobic/hydrophilic compositionsare used for AqpZ reconstitution, as shown in Table 1.

    Table 1. ABA triblock copolymers used for preparation of AqpZ reconstituted vesicles.
    Name ABA triblock copolymers Hydrophobic molecular weight of the polymer (Da.) fhydrophilic (Hydrophilic mass ratio)
    P2500 [a] PMOXA500-PDMS2500-PMOXA500 [c] 2500 28.57 %
    P4000 [b] PMOXA1000-PDMS4000-PMOXA1000 [c] 4000 33.33 %
    P5000 [b] PMOXA1300-PDMS5000-PMOXA1300 [c] 5000 34.21 %
    P8500 [a] PMOXA1300-PDMS8500-PMOXA1300 [c] 8500 23.40 %
    P8800 [a] PMOXA2000-PDMS8800-PMOXA2000 [c] 8800 31.25%
    [a] tri-block copolymers P2500, P8500 and P8800 are with hydroxyl end groups;
    [b] tri-block copolymers P4000 and P5000 are with methacrylate end groups which allow for a UV light induced polymerization;
    [c] In “PMOXAxxx-PDMSxxxx-PMOXAxxx”, the number after each block represents the molecular weight (Da.) of each block.
     | Show Table
    DownLoad: CSV

    2.3. Preparation of blank polymer v esicles and AqpZ-reconstituted polymer vesicles

    The blankcopolymer vesicles were prepared using the film rehydration method shown in Figure 1. Each kind of polymer (3 mg) was dissolved in chloroform (5 ml)in a round bottomed flask. Chloroform was then evaporated slowly in a rotary vacuum evaporator at -10°C and at a vacuum of 400 mbar, to form an even andthin film of polymer at the bottom of the flask. Theresidual chloroform was further removed using a vacuum pump. The film was then rehydrated by the respective pH buffer(prepared from sodium chloride with hydrogen chloride or sodium hydroxide, with total ion concentration of 0.2 mol/L) solutions or deionized water, forming suspension with polymer concentration of 1 mg/ml. The mixture was left at room temperature with stirring for 10 h. The resultant polymersome suspension was extruded 21 times with a polycarbonate membrane with pore diameter of 200 nm to achieve unilamellar vesicles with a narrow size distribution.

    Figure 1. Schematic diagram for reconstitution of AqpZ into vesicles that are made from amphiphilic block copolymers.

    The preparation procedure for proteopolymersomes was similar as above. The only difference was in the reconstitution experiments, where an appropriate amount of AqpZ solution (1 mg/ml in 2% DDM (dodecyl maltoside) wasadded to the samples duringrehydration. The detergent was removed by adding bio-beads into the mixture. The bio-beads were added every 4 h for 5 times, to allow for the adsorption process to reach equilibrium each time before the next batch of bio-beads adding into the suspension. Bio-beads were added in 5-fold excess in the last batch to ensure that the remaining detergent molecules will be adsorbed and removed entirely.The proteopolymersomes were then extruded with the same method as in the preparation of the blank polymersomes.

    2.4. UV-crosslinking of polymer vesicles

    The extruded P4000 and P11500 polymersome suspensions were purged with argon for 10 min and further crosslinked under UV irradiation (254 nm, 6 mW cm-2) for 15 min using a BLX-E254 crosslinker (Vilber Lourtmat, France). The polymer vesicles before and after UV irradiation were freeze-dried and characterized using a Fourier transform infrared spectrometer (FTIR-8400 Shimadzu Corp., Japan) to determine the crosslinking reaction between the methacrylate groups.

    2.5. Size and morphology c haracterization of polymersomes

    Vesicle size was measured by a dynamic light scattering unit (Zetasizer 3000 HAS equipped with a He-Ne laser beam at 658 nm, Malvern Instruments Ltd., Malvern, UK; scattering angle: 90°). Vesicle suspensions were diluted to 0.01 mg/ml with DI water or respective buffer solution for the dynamic light scattering tests. An average value was obtained from three measurements.

    Vesicle morphologies were measured using field emission transmission electron microscopy (FETEM), whereby the vesicles were stained on plasma-treated copper grids using 1% trifluoroacetic acid.

    2.6. Characterization of permeability coefficient (Pf) of vesicles, permeability of reconstituted aquaporin Z (Pa) and the Arrhenius activation energy (Ea) of water molecules across polymer vesicles

    The permeability coefficients of various polymer vesicles with or without AqpZ reconstitution were characterized using the stopped-flow (Chirascan Circular Dichroism Spectrometer, Applied Photophysics, UK) method. For each individual stopped-flow test, 0.13 ml extruded polymersome or proteopolymersome solution with polymer concentration of 1 mg/ml was quickly mixed with 0.13 ml sucrose buffer (0.6 osmol/L), which caused water efflux from vesicles that resulted in vesicle shrinkage. At least 6 tests were performed for each sample. The dead time for the mixing of stopped flow injection was 4 ms. The vesicle size changes were monitored and recorded in the form of an increasing signal in the light scattering analysis. The initialrise of the signal curve was fitted to equation (1).

    Y=Aexp(kt)
    (1)

    Where Y is the signal intensity, A is the negative constant, k is the initial rate constant (s-1), and t is the recording time. The osmotic water permeability was calculated using Equation (2).

    Pf=k(S/V0)VwΔosm
    (2)

    Where Pf is the osmotic water permeability (m/s), S is the vesicle surface area (m2), V0 is the initial vesicle volume (m3), Vw is the partial molar volume of water (0.018 L/mol), and Δosm is the osmolarity difference that drives the shrinkage of the vesicles (osmol/L).

    Single AqpZ channel permeability was calculated using Equation (3) [33].

    Pa=Pf,proteopolymersomePf,polymersomeMon/A
    (3)

    Pf, proteopolymersome is the permeability of the AqpZ-vesicles, Pf, polymersome is the permeability of the polymersomes without AqpZ reconstitution, and Mon/A is the number of AqpZ monomers per unit area in the proteopolymersomes.

    To measure the Arrhenius activation energy of water molecules across polymer vesicles, Stopped-flow experiments were carried out at different temperatures (5, 10, 15, 20, 25 and 30 °C) for both blank polymer vesicles and AqpZ-reconstituted polymer vesicles. The exponential increase rates (k) calculated from the light scattering signals were plotted against the inverse of temperature for calculation of the Arrhenius activation energies. The comparative experiments were all tested at room temperature.

    2.7. Statistical analysis

    All the data presented in this study represent the mean ± standard deviation values of three experiments, unless stated otherwise. Statistical differences between groups were found using a Student’s t-test.

    3. Results and Discussion

    In this study, detailed investigation was carried out on the mechanism of water transport through AqpZ reconstituted polymer bilayers. Our aim was to establish a relationship between membrane matrix properties and the AqpZ functionality, as well as the relationship between the AqpZ permeability and the environmental conditions. Triblock copolymer PMOXA-PDMS-PMOXA is the most commonly used membrane matrix for AqpZ incorporation. The molecular structure including molecular weight, hydrophilic-lipophilic balance, functional end group and crosslinking capability, has to be considered carefully to ensure the successful incorporation of aquaporins into the vesicles to maintain its structure and function. We incorporated AqpZ into a series of PMOXA-PDMS-PMOXA block copolymers, adjusted the pH value of vesicle solutions, and controlled the temperature during stopped flow measurement, in order to investigate the influence of molecular structure of the membrane matrixand the external conditions onthe osmotic permeability of the reconstituted AqpZ.

    3.1. Block copolymer composition vs. vesicle formation and morphology

    Amphiphilic block copolymers have similar behaviour as lipids, which are also amphiphilic. In aqueoussolutions, amphiphilic block copolymers will self-assemble into various ordered morphologies, such as micelles, vesicles and lamellar phases. Three parameters of block copolymers play important roles in the phase transition between these morphologies, including the molecular weight of the polymer, the mass fraction (f) of each block, and the effective interaction energy between the repeating units in the blocks [34]. PMOXA-PDMS-PMOXA has been widely adopted to form vesicle bilayers for the reconstitution of transmembrane proteins [1,27,29] through self-assembly. In this section, we systematically investigated how the polymer molecular weight and the mass fraction of each block influence the self-assembly, and how the molecular weight of the hydrophobic block effects the AqpZ permeability.

    A series of block copolymers PMOXA-PDMS-PMOXA with various molecular weight andhydrophobic/hydrophilic ratio were chosen to prepare proteopolymersomes, as listed in Table 1. The hydrophilic ratio (fhydrophilic) of these polymers ranges from 23.4 to 34.2% in the sequence of P8500 < P2500 < P8800 < P4000 < P5000. Figure 2 shows the morphologies of the self-assemblies without extrusion. It can be seen that all of them form vesicles except for P8500. This result is consistent with previous report in that the fhydrophilic range of block copolymer to form vesicles is between 25 to 40% [35]. With increasing fhydrophilic, vesicle size decreases sequentially as P2500 > P8800 > P4000 > P5000. According to the simulation results from our previous work, larger vesicles are preferable since larger vesicles will generate higher water flux as compared to smaller ones in an AqpZ-incorporated-vesicular membrane [27]. Therefore, block copolymers with fhydrophilic ranging from 25 to 30% are preferable for preparation of AqpZ-incorporated-vesicular membrane.

    Figure 2. Morphologies of polymersomes by transmission electron microscope (TEM). Polymersomes are made from PMOXA-PDMS-PMOXAs with various molecular weights: (a) P2500; (b) P4000; (c) P4000 after exposure to UV irradiation; (d) P8800; (e) P8500; (f) P5000; (g) P5000 after exposure to UV irradiation.

    The vesicle wall thickness is greatly influenced by the molecular weight of the hydrophobic block of PDMS in the PMOXA-PDMS-PMOXA. Figure 3 shows the correlation between the molecular weight of the hydrophobic block and the vesicle wall thickness measured from TEM. It can be seen that, vesicle wall thickness increases from 5.2 nm to 11.6 nm when the molecular weight of the hydrophobic block PDMS increases from 2500 to 8800. A longer hydrophobic chain length leads to a thicker membrane wall and a higher packing density due to chain entanglement, which is consistent with other reports [34]. In addition, the triblock copolymers P4000 and P5000 have methacrylate end groups thatallow for a UV light-induced polymerization. After UV light exposure, the methacrylate end groups distributed at the vesicle surface will be polymerized with neighbouring methacrylate end groups and form a covalent bond shell on the vesicle surface, which will enhance the mechanical stability of vesicles. In Figure 3, the red points refer to the wall thickness of vesicles that are formed from methacrylate-copolymers after UV exposure. It is noted that for vesicles prepared from methacrylate-copolymers, P4000 and P5000, vesicle wall thickness increases after UV polymerization of the methacrylate end groups as compared to vesicles without or before polymerization.

    Figure 3. Relationship between the molecular weight of the hydrophobic PDMS block in the ABA triblock copolymers and the thickness of the hydrophobic layer in the vesicle membrane (vesicle wall thickness). The vesicle wall thicknesses were measured from TEM images by using Photoshop software. 10 points were randomly selected for each sample. Values are represented with the mean ± standard deviation (n = 10).

    3.2. Vesicle wall thickness and AqpZ permeability

    The hydrophobic thickness of the polymer vesicles, as shown in Figure 3,is thicker than that of lipid bilayers, which is 3 nm [36]. When AqpZ is reconstituted into polymer vesicles, there is hydrophobic mismatch between the hydrophobic length of the AqpZ and the hydrophobic thickness of the membrane, as shown in Figure 4. It has been reported that the membrane protein with hydrophobic mismatch towards the neighbouring bilayer will distort the bilayer at the interface, resulting in the bilayer morphology not being aligned correctly with the protein [37]. It has also been reported that the elastic lipid chain distortions are insufficient to compensate fully for the mismatch [38], and the structure and dynamics of protein might change due to this hydrophobic mismatch [39,40]. The stretched or compressed structure of AqpZ might affect water transport behavior of the water channels. In this work, the permeability of AqpZ that reconstituted in these polymers was therefore investigated through the vesicle permeability using stopped-flow spectroscopy.

    Figure 4. Schematic diagram of hydrophobic mismatch between the reconstituted AqpZ and the hydrophobic layer of the vesicle membrane.

    Figure 5 shows examples of the light scattering intensity curves for blank polymersomes (Figure 5a) and proteopolymersomes (Figure 5b). It can be observed from Figure 5a that with increasing hydrophobic chain length, vesicle size responds slower to the osmotic pressure. When the hydrophobic chain length is above 5000 Da, vesicle size almost does not respond to the osmotic pressure, indicating an extremely slow water diffusion speed across the thick hydrophobic wall and a negligible water permeability of the blank polymersomes. From Figure 5b,it can be observed that all AqpZ reconstituted vesicles shrink more quickly than the blank vesicles under the osmotic pressure. This proves that AqpZ has been successfully reconstituted to maintain its water transport functionality in these polymer vesicles. According to Figure 3,vesicle wall thickness ranges from 5.2 to 11.6 nm, which is much thicker than the lipid bilayer. The stopped-flow results gave us confidence that the hydrophobic mismatch, which is less than 9 nm, will not lead to AqpZ misfolding or denaturation.

    Figure 5. Water permeability of the vesicles determined by a stopped-flow spectroscopy. The increase in the light scattering signal represents a reduction in vesicle size due to water efflux from the vesicle to the solution. The data were exponentially fitted by equation (1). The solid lines represent fitting curves. (a) The relative light scattering signals of blank vesicles without AqpZ incorporation; (b) The relative light scattering signals of AqpZ-reconstituted vesicles at a protein-polymer molar ratio of 1:200.

    Figure 6 shows permeabilities for both types of vesicles (Figure 6a) and each AqpZ unit in proteopolymersomes (Figure 6b). In this work, the molecular weight of the hydrophobic block PDMS ranges from 2500 to 8800 Da. Correspondingly, vesicle wall thickness ranges from 5.2 nm to 11.6 nm. A stretched AqpZ structure might take place due to the hydrophobic mismatch between the AqpZ protein and a thick hydrophobic layer of the vesicle membrane. In order to investigate whether the stretched structure of AqpZ affected the water transport behavior of the water channels, we calculated the water permeability of each AqpZ unit (Pa) in these vesicles. The Pa value ranges from 6.9 to 14 × 10-14 cm3 s-1 which is consistent with Verkman’s results (from 6 to 24 × 10-14 cm3 s-1) [41], indicating that the hydrophobic mismatch, in our experiment range, will not lead to AqpZ misfolding or denaturation. Moreover, from Figure 6b,we find that a thicker vesicle wall leads to a larger Pa value, indicating that the hydrophobic mismatch in our experiment range enhances the water permeability of the AqpZ channel. The reason could be due to the water channel being distortedand expanded to a small extent, forming a “stretched structure” of AqpZ. Further evidence will be needed to confirm this hypothesis of a stretched AqpZ structure in the polymer bilayers.

    Figure 6. (a) Permeability coefficient (Pf) of vesicles, and (b) permeability of each AqpZ unit (Pa). Pf and Pa are determined by stopped-flow spectroscopy. The light scattering signals from stopped-flow were exponentially fitted by equation (1). Pf and Pa are calculated by using equation (2) and equation (3), respectively. All the experiment data have been repeated 3 times. Values represent the mean ± standard deviation (error bars) with n = 3.

    3.3. Hydrophobic mismatch vs. Arrhenius activation energies for water molecule across the vesicle

    To investigate the activation energies for water transport in both the polymer bilayers and the AqpZ channels, stopped-flow spectroscopy and light scattering analysis were performed at various temperatures ranging from 278 K to 303 K. Figure 7 was plotted using the derived ln k values against the inverse temperature values, 1/T, where k is the initial rate constant (s-1) of the light scattering intensity signal, and T is the temperature. The observed trends for the ln k values of the blank polymer vesicles and AqpZ-reconstituted polymer vesicles to the variation in experimental temperatures were consistent for all the ABA copolymers used, and exhibited similar linearly decreasing trends. When temperature increases, more heat energy is provided to the water molecules present. The heat energy gained by the water molecules gets converted to kinetic energy, leading to an increase in the rate of transport of the water molecules across the membrane through the AqpZ channels. In addition, higher temperature provides higher kinetic energy to the water molecules, leading to greater frequency and impact of the water molecules against the bilayer structure. Therefore, this gives rise to a greater number of water molecules passing through the bilayer structure through the pores present between the polymers, without going through AqpZ proteins.

    Figure 7. Arrhenius plots for calculation of activation energy for osmotic transport of water across AqpZ-reconstituted polymer vesicles and blank polymer vesicles. In AqpZ-reconstituted vesicles, the protein-polymer molar ratio was 400:1. Polymers used in these vesicles were (a) P2500, (b) P4000, (c) P5000 and (d) P8800. All the experimental data have been repeated 3 times. Values represent the mean value.

    As shown in Figure 8,the calculated Arrhenius activation energies for blank polymer bilayers ranges from 6.4 to 52.8 kcal/mol, which is consistent with the reported activation values for water transport across polymer membranes [42]. The high Arrhenius activation energies of blank polymer vesicles indicate that the water transport through polymer bilayers is based on a diffusion-driven mechanism. It can also be observed that higher Arrhenius activation energies were obtained from the polymer vesicles with higher hydrophobic molecular weight, compared to those polymer vesicles with lower hydrophobic molecular weight. The denser packing of the longer hydrophobic chain and the thicker membrane hydrophobic thickness form a larger barrier for diffusion, requiring higher activation energies for water molecules passing through. Arrhenius activation energies for AqpZ reconstituted polymer vesicles range from 2.1 to 6.1 kcal/mol. These lower Arrhenius activation energies indicate that water transport across the AqpZ reconstituted vesicles is channel-mediated. Borgnia et al. reported that the activation energy for AqpZ channel is 3.7 kcal/mol in proteoliposomes [12] and thus our results are comparable to the reported value. In addition, when AqpZ were reconstituted into block copolymers with longer hydrophobic chains, a lower Arrhenius activation energy was required for water molecules to pass through the AqpZ channel. It again implies that the structure of AqpZ channel might be stretched to some extent due to the hydrophobic mismatch, leading to a wider channel for the water molecule to pass through. To confirm this hypothesis, further investigations using x-ray crystallography, NMR spectroscopy and molecular dynamics simulation will be needed.

    Figure 8. Arrhenius activation energy for osmotic transport of water across AqpZ-reconstituted polymer membranes and blank polymer membranes with various hydrophobic chain lengths.

    3.4. ipH value of environmental solution vs. AqpZ permeability

    Figure 9a shows the permeability coefficients of the AqpZ-reconstituted P4000 vesicle in buffer solutions with different pH values. The highest Pf appears near neutral conditions when the pH is 7.5. With increasing concentration of H+, the Pf greatly decreased at pH of 5.5, and increased again in the strongly acidic environment with pH less than 3.5. On the other hand, with increasing concentration of OH- in the vesicle solution, the Pf value also greatly decreased at pH of 8.9 and followed by a slight increase at the strongly basic environment with a pH of more than 10. Further, we calculated the osmotic permeability of AqpZ channel (Pa) based on the Pf value. As shown in Figure 9b,the Pa versus the pH shows the same trend as the vesicle permeability coefficient (Pf). This shows that thewater filtration mechanism of AqpZ is significantly affected by the ions of H+ and OH-.

    Figure 9. (a) Vesicle permeability coefficient (Pf), and (b) permeability of each AqpZ unit (Pa) versus pH value of the buffer solution. Proteopolymersomes were made from P4000. The polymer to protein molar ratio was 400:1. All the experiment data have been repeated 3 times. Values represent the mean ± standard deviation (error bars) with n=3.

    The observed trends for the regulation in the osmotic permeability of the AqpZ-ABA vesicles (Figure 9a) and the individual AqpZ proteins (Figure 9b) are similar with respect to the variation in pH. The tendency of the osmotic permeability to decrease with increasing pH values may be attributed to the structure of AqpZ. Near the constriction of the AqpZ hydrophobic channel, there are histidine (H) and arginine (R) residues present in the AqpZ monomer loops at positions H180 and R195 respectively that provide the positive charges required in the water transport mechanism of AqpZ [14,15]. Histidine has an overall pI value of 7.6 with their imidazole side chains having a pKa of about 6.0, while arginine has an overall pI value of 10.8 with their guanidinium side chains having a pKa of 12.5. Hence, the positive charges present on the residues will change with pH due to the effects of protonation.

    The change in the protonation status of the -COOH terminal group of the amino acid residues as pH changes, may have an effect on the water-pore interaction and the formation of the single file configuration of water molecules passing through the AqpZ channel. Thus AqpZ water transport efficiency was affected since the separation capabilities of AqpZ stems from the formation of thesingle file of water molecule, which prohibits proton translocation and is dependent on the positive charges present at positions H180 and R195 [14,15].

    4. Conclusion

    There is an increasing pressure to innovate cheaper forms of membrane technologies to address the issue of water scarcity. Biomimetic membrane technologies utilizing aquaporin is an attractive alternative that can carry out filtration at high capacities using a lower pressure gradient. For AqpZ to be exploited successfully in membrane filtration, an understanding of the factors that influence the osmotic permeability of AqpZ is critical. This study investigated the influences of factors such as pH, temperature, crosslinking and the molecular structure of the ABA tri-block copolymers (PMOXA-PDMS-PMOXA) in which the AqpZ was incorporated, on the osmotic permeability of AqpZ. Results show that the molecular structure of PMOXA-PDMS-PMOXA significantly alters the vesicle morphology and aquaporin functionality. Block copolymers with longer hydrophobic chains form vesicles with thicker hydrophobic walls, resulting in larger hydrophobic mismatch between the protein and the bilayer membrane. The stopped flow results show that the osmotic permeability of AqpZ has improved when reconstituted in a bilayer with a larger hydrophobic thickness. The Arrhenius activation energies for water transport across the AqpZ channel showa decreasing trend with increasing hydrophobic thickness of the bilayers, indicating a “stretched structure” of the AqpZ when encountering a lengthening hydrophobic mismatch. In addition, we found that the water filtration mechanism of the AqpZ protein is significantly affected by the ionic concentrations of H+ and OH-. The individual AqpZ exhibits the highest osmotic permeability in neutral solution. The ApqZ osmotic permeability decreased with eitherincreasing concentrations of H+, or increasing concentrations of OH-.

    Acknowledgements

    This work was financially supported by Singapore's National Research Foundation (NRF) through the Environment and Water Industry Programme Office (EWIPO) EWI projects, 1102-IRIS-13-01 and 1102-IRIS-13-02 as well as the NUS grant R706000022279. The authors would like to thank Prof. T. S. Chung, Drs Q. Lin, H. Wang, H. Zhou, L. Wang for their suggestions and help with this work.

    Conflict of Interest

    All authors declare no conflicts of interest in this paper.

    [1] Environmental health/indoor air/mold house and water damage. From the National Institute of Health and Welfare. Available from: https://thl.fi/fi/web/ymparistoterveys/sisailma/hometalo-ja-kosteusvaurio Assessed 12.10.2018.
    [2] Reijula K (1996) Health risks and diagnostics of diseases caused by moisture and mold damage buildings. Kosteus-ja homevauriorakennuksien aiheuttamat terveysriskit ja sairauksien diagnostiikka. Duodecim 112: 1390–1397.
    [3] Becher R, Høie AH, Bakke JV, et al. (2017) Dampness and moisture problems in Norwegian homes. Int J Environ Res Public Health 14: 1241. doi: 10.3390/ijerph14101241
    [4] WHO (2009) WHO guidelines for indoor air quality: Dampness and mould. World Health Organization 2009. Copenhagen, Denmark. ISBN-13: 978-92-890-4168-3.
    [5] Reponen T, Levin L, Zheng S, et al. (2013) Family and home characteristics correlate with mold in homes. Environ Res 124: 67–70. doi: 10.1016/j.envres.2013.04.003
    [6] Available from: http://www.sisailmayhdistys.fi/Terveellisettilat/Kosteusvauriot/Mikrobit/ Microbial growth conditions. Assessed 23.7.2018 (Finnsh).
    [7] Finnish Broadcasting from YLE. Available from: https://yle.fi/uutiset/3-9885382. Assessed 23.7.2018 (Finnish).
    [8] Kuhn DM, Ghannoum MA (2003) Indoor mold, toxigenic fungi, and Stachybotrys chartum: Infectious disease perspective. Clin Microbiol Rev 16: 144–172. doi: 10.1128/CMR.16.1.144-172.2003
    [9] Miller CS (2001) The compelling anomaly of chemical intolerance. Ann N Y Acad Sci 933: 1–23.
    [10] Global Indoor Health Network (GIHN) Diagnosis and Treatment of Illness Caused by Contaminants in Water-Damaged Buildings. "Working Together for Healthy Indoor Environments" PO Box 777308 Henderson, NV 89077-7308, Available from: https://www.globalindoorhealthnetwork.com/.
    [11] Valtonen V (2017) Clinical diagnosis of the Dampness and Mold Hypersensitivity Syndrome: Review of the literature and suggested diagnostic criteria. Front Immunol 8: 951. doi: 10.3389/fimmu.2017.00951
    [12] Park JH, Cox-Ganser JM (2011) Mold exposure and respiratory health in damp indoor environments. Front Biosci (Elite Ed) 3: 757–771.
    [13] Fisk WJ, Lei-Gomez Q, Mendell MJU (2007) Meta-analyses of the associations of respiratory health effects with dampness and mold in homes. Indoor Air 17: 284–296. doi: 10.1111/j.1600-0668.2007.00475.x
    [14] Fisk WJ, Elisevaara A, Mendel MJ (2010) Association of residential dampness and mold with respiratory tract infections and bronchitis: A meta-analysis. Environ Health 15: 1–11.
    [15] Hurraβ J, Heinzow B, Aurbach U, et al. (2017) Medical diagnostics for indoor mold exposure. Int J Hyg Envir Health 220: 305–328. doi: 10.1016/j.ijheh.2016.11.012
    [16] Mendell MJ, Mirer AG, Cheung K, et al. (2011) Respiratory and allergic health effects of dampness, mold, and dampness-related agents: A review of the epidemiologic evidence. Environ Health Persp 119: 748–756. doi: 10.1289/ehp.1002410
    [17] Alenius H, Haahtela T, Hakulinen A, et al. (2007) Recommendations of Majvik II-Identifying symptoms related to moisture damage microbes. Majvik II-suositus: Kosteusvauriomikrobeihin liittyvien oireiden selvittely SLL 7: 655–664.
    [18] Park JH, Cho SJ, White SK, et al. (2018) Changes in respiratory and nonrespiratory symptoms in occupants of a large office building over a period of moisture damage remediation attempts. PLoS One 13: e0191165. doi: 10.1371/journal.pone.0191165
    [19] Aggarwald AN, Chakrabarti A (2013) Does climate mould influence of mold on asthma? Lung India 30: 273–276. doi: 10.4103/0970-2113.120594
    [20] Empting LD (2009) Neurologic and neuropsychiatric syndrome features of mold and mycotoxin exposure. Toxicol Int Health 25: 577–581. doi: 10.1177/0748233709348393
    [21] Tuuminen T, Rinne KS (2017) Severe sequelae to mold-related illness as demonstrated in two finnish cohorts. Front Immunol 8: 382.
    [22] Tuuminen T, Jääskeläinen T, Vaali K, et al. (2018) Dampness and mold hypersensitivity syndrome and vaccination as risk factors for chronic fatigue syndrome. Autoimmun Rev 5: S1568–S9972.
    [23] Thrasher JD, Gray MR, Kilburn KH, et al. (2012) A water-damaged home and health of occupants: A case study. J Environ Public Health 2012: 10.
    [24] Pitkäranta A, Hytönen M, Näin hoidan (2006) Pitkittynyt nuha. Duodecim 122: 827.
    [25] Shaaban R, Zureik M, Soussan D, et al. (2008) Rhinitis and onset of asthma: A longitudinal population-based study. Lancet 372: 1049–1057. doi: 10.1016/S0140-6736(08)61446-4
    [26] Brewer JH, Thrasher JD, Hooper D (2013) Chronic illness associated with mold and mycotoxins: Is naso-sinus fungal biofilm the culprit? Toxins 24: 66–80.
    [27] Kwon JW, Kim TW, Kim KM, et al. (2012) Differences in airway inflammation according to atopic status in patients with chronic rhinitis. Asia Pac Allergy 2: 248–255. doi: 10.5415/apallergy.2012.2.4.248
    [28] Lanthier-Veilleux M, Baron G, Généreux M (2016) Respiratory diseases in university students associated with exposure to residential dampness or mold. Int J Environ Res Public Health 13: 1154. doi: 10.3390/ijerph13111154
    [29] Jalanko H (2017) Infections in child. Infektiokierre lapsella. Duodecim Terveyskirjasto. Available from: https://www.terveyskirjasto.fi/kotisivut/tk.koti?p_artikkeli=dlk00131.
    [30] Löwhagen O (2015) Diagnosis of asthma-new theories. J Asthma 52: 538–544. doi: 10.3109/02770903.2014.991971
    [31] Hasegawa T, Uga H, Mori A, et al. (2017) Increased serum IL-17A and Th2 cytokine levels in patients with severe uncontrolled asthma. Eur Cytokine Netw 28: 8–18.
    [32] Reponen T, Vesper S, Levin L, et al. (2011) High environmental relative moldiness index during infancy as a predictor of asthma at 7 years of age. Ann Allerg Asthma Im 107: 120–126. doi: 10.1016/j.anai.2011.04.018
    [33] Hsu J, Chen J, Mirabelli MC (2018) Asthma morbidity, comorbidities, and modifiable factors among older adults. J Allergy Clin Immun 6: 236–243. doi: 10.1016/j.jaip.2017.06.007
    [34] Kanchongkittiphon W, Mendell MJ, Gaffin JM, et al. (2015) Indoor environmental exposures and exacerbation of asthma: An update to the 2000 review by the institute of medicine. Environ Health Persp 123: 6–20. doi: 10.1289/ehp.1307922
    [35] Bush RK, Portnoy JM, Saxon A, et al. (2006) The medical effects of mold exposure. J Allergy Clin Immun 117: 326–333. doi: 10.1016/j.jaci.2005.12.001
    [36] Eerikäinen J, Nynäs P, Uitti J (2013) Subacute allergic alveolitis caused by work-related moisture damage microbes. Työperäinen kosteusvauriomikrobien aiheuttama subakuutti allerginen alveoliitti. Duodecim 129: 972–975.
    [37] Selman M, Pardo A, King Jr TE (2012) Hypersensitivity pneumonitis: Insights in diagnosis and pathobiology. Am J Resp Crit Care 186: 314–324.
    [38] Thörn Å, Lewene M, Belin L (1996) Allergic alveolitis in a school environment. Scand J Work Environ Health 22: 311–314. doi: 10.5271/sjweh.146
    [39] Reijula K, Sutinen S (1986) Ultrastructure of extrinsic allergic bronchiolo-alveolitis. Pathol Res Pract 181: 418–429. doi: 10.1016/S0344-0338(86)80077-2
    [40] Galeazzo G, Sforza R, Marinou A (2017) Hypersensitivity pneumonitis: A complex lung disease. Clin Mol Allergy 15: 1–8. doi: 10.1186/s12948-016-0057-9
    [41] Kumar V, Aster JC, Fausto N, et al. (2014) Robbins and cotran pathologic basis of disease, Professional Edition. Elsevier LTD, Oxford.
    [42] Agarwal R, Chakrabarti A, Shah A, et al. (2013) Allergic bronchopulmonary aspergillosis: Review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy 43: 850–873. doi: 10.1111/cea.12141
    [43] Greenberger PA, Bush RK, Demain JG, et al. (2014) Allergic bronchopulmonary aspergillosis. J Allergy Clin Immun 2: 703–708. doi: 10.1016/j.jaip.2014.08.007
    [44] Chowdhary A1, Agarwal K, Kathuria S, et al. (2014) Allergic bronchopulmonary mycosis due to fungi other than aspergillus: A global overview. Crit Rev Microbiol 40: 30–48. doi: 10.3109/1040841X.2012.754401
    [45] Nordman H, Uitti J, Toskala-Hannikainen E, et al. (2007) Kosteusvauriomikrobien aiheuttamien sairauksien tutkiminen. SLL 9: 911–918.
    [46] Kankkunen P, Teirilä L, Rintahaka J, et al. (2010) (1,3)-beta-glucans activate both dectin-1 and NLRP3 inflammasome in human macrophages. J Immunol 184: 6335–6342. doi: 10.4049/jimmunol.0903019
    [47] Korkalainen M, Täubel M, Naarala J, et al. (2017) Synergistic proinflammatory interactions of microbial toxins and structural components characteristic to moisture-damaged buildings. Indoor Air 27: 13–23. doi: 10.1111/ina.12282
    [48] Gray MR, Thrasher JD, Crago R, et al. (2003) Mixed mold mycotoxicosis: Immunological changes in humans following exposure in water-damaged buildings. Arch Environ Health 58: 410–420. doi: 10.1080/00039896.2003.11879142
    [49] Trasher JD (2016) Fungi, bacteria, nanoparticulates, mycotoxins and human health in water damaged indoor environments. J Comm Pub Health Nurs. researchgate.net.
    [50] Pestka JJ, Yike I, Dearborn DG, et al. (2008) Stachybotrys chartarum, trichothecene mycotoxins, and damp building-related illness: new insights into a public health enigma. Toxicol Sci 104: 4–26. doi: 10.1093/toxsci/kfm284
    [51] Edmondson DA, Barrios CS, Brasel TL, et al. (2009) Immune response among patients exposed to molds. Int J Mol Sci 10: 5471–5484. doi: 10.3390/ijms10125471
    [52] Ammann HM (2002) Indoor mold contamination-a threat to health? J Environ Health 64: 43.
    [53] Ammann HM (2003) Indoor mold contamination-a threat to health? Part two. J Environ Health 66: 47.
    [54] Ammann HM (2016) Inhalation exposure and toxic effects of mycotoxins. Biol Microfungi 495–523.
    [55] Mikkola R, Andersson MA, Grigoriev P, et al. (2017) The mitochondrial toxin produced by Streptomyces griseus strains isolated from an indoor environment is valinomycin. J Appl Microbiol 123: 436–449. doi: 10.1111/jam.13498
    [56] Islam Z, Harkema JR, Pestka JJ (2006) Satratoxin G from the black mold stachybotrys chartarum evokes olfactory sensory neuron loss and inflammation in the murine nose and brain. Environ Health Persp 114: 1099–1107. doi: 10.1289/ehp.8854
    [57] Jarvis BB (2003) Analysis for mycotoxins: The chemist's perspective. Arch Environ Health 58: 479–483. doi: 10.3200/AEOH.58.8.479-483
    [58] Kankkunen P, Välimäki E, Rintahaka J, et al. (2014) Trichothecene mycotoxins activate NLRP3 inflammasome through a P2X7 receptor and Src tyrosine kinase dependent pathway. Hum Immunol 75: 134–140.
    [59] Wong J, Magun BE, Wood LJ (2016) Lung inflammation caused by inhaled toxicants: A review. Int J Chron Obstruct Pulmon Dis 11: 1391–1401.
    [60] Huttunen K, Hyvärinen A, Nevalainen A, et al. (2003) Production of proinflammatory mediators by indoor air bacteria and fungal spores in mouse and human cell lines. Environ Health Persp 111: 85–92. doi: 10.1289/ehp.5478
    [61] Li M, Harkema JR, Islam Z, et al. (2006) T-2 toxin impairs murine immune response to respiratory retrovirus and exacerbates viral bronchiolitis. Toxicol Appl Pharm 217: 76–85. doi: 10.1016/j.taap.2006.08.007
    [62] Wang H, Yadav JS (2006) DNA damage, redox changes, and associated stress-inducible signaling events underlying the apoptosis and cytotoxicity in murine alveolar macrophage cell line MH-S by methanol-extracted Stachybotrys chartarum toxins. Toxicol Appl Pharm 214: 297–308. doi: 10.1016/j.taap.2006.01.002
    [63] Penttinen P, Tampio M, Mäki-Paakkanen J, et al. (2007) DNA damage and p53 in RAW264.7 cells induced by the spores of co-cultivated Streptomyces californicus and Stachybotrys chartarum. Toxicol 235: 92–102.
    [64] Penttinen P, Pelkonen J, Huttunen K, et al. (2005) Interactions between streptomyces californicus and Stachybotrys chartarum can induce apoptosis and cell cycle arrest in mouse RAW264.7 macrophages. Toxicol Appl Pharm 202: 278–288. doi: 10.1016/j.taap.2004.07.002
    [65] Ndika J, Suojalehto H, Täubel M, et al. (2018) Nasal mucosa and blood cell transcriptome profiles do not reflect respiratory symptoms associated with moisture-damage. Indoor Air, May 4. doi: 10.1111/ina.12472.
    [66] Hellgren UM, Leino M, Aarnisalo AA, et al. (2009) Low tumor necrosis factor alpha levels and neutrophil counts in nasal lavage after mold exposure. Ann Allergy Asthma Im 102: 210–215. doi: 10.1016/S1081-1206(10)60083-X
    [67] Schütze N, Lehmann I, Bönisch U, et al. (2010) Exposure to mycotoxins increases the allergic immune response in a murine asthma model. Am J Resp Crit Care 181: 1188–1199.
    [68] Bhan U, Newstead MJ, Zeng X, et al. (2011) Stachybotrys chartarum-induced hypersensitivity pneumonitis is TLR9 dependent. Am J Pathol 179: 2779–2787. doi: 10.1016/j.ajpath.2011.08.019
    [69] Vincent M, Percier P, De Prins S, et al. (2017) Investigation of inflammatory and allergic responses to common mold species: Result from in vitro experiments, from a mouse model of asthma, and from a group of asthmatic patients. Indoor Air 27: 933–945. doi: 10.1111/ina.12385
    [70] Taskinen T. Moisture and mould problem in school children. Väitöskirja. Kuopio KTL. A9/2001. (Academic dissertation).
    [71] Flamant-Hulin M, Anniesi-Maesano I, Caillaud D (2013) Relationships between molds and asthma suggesting non-allergic mechanisms. A rural-urban comparison. Pediatr Allergy Immu 24: 345–352. doi: 10.1111/pai.12082
    [72] Weinmayr G, Gehring U, Genuneit J, et al. (2013) Dampness and moulds in relation to respiratory and allergic symptoms in children: A result from Phase two of the international study of asthma and allergies in childhood (ISAAC phase two). Clin Exp Allergy 43: 762–774. doi: 10.1111/cea.12107
    [73] Andersson MA, Mikkola R, Helin J, et al. (1998) A novel sensitive bioassay for detection of Bacillus cereus emetic toxin and related depsipeptide ionophores. Appl Environ Microb 64: 1338–1343.
    [74] Andersson MA, Mikkola R, Kroppenstedt RM, et al. (1998) The mitochondrial toxin produced by Streptomyces griseus strains isolated from an indoor environment is valinomycin. Appl Environ Microb 64: 4767–4773.
    [75] Korppi M, Dunder T, Remes S, et al. (2011) Congenital dysfunction of ciliary cells in children Värekarvojen synnynnäiset toimintahäiriöt lapsilla. Duodecim 127: 2294–2302.
    [76] Piecková E (2003) In vitro toxicity of indoor Chaetomium Kunze ex Fr. Ann Agr Env Med 10: 9–14.
    [77] Piecková E, Wilkins K (2004) Airway toxicity of house dust and its fungal composition. Ann Agr Env Med 11: 67–73.
    [78] Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140: 805–820. doi: 10.1016/j.cell.2010.01.022
    [79] Zhang Z, Myers JMB, Brandt EB, et al. (2017) β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses. J Allerg Clin Immun 139: 54–65. doi: 10.1016/j.jaci.2016.02.031
    [80] Martin TR, Frevert CW (2005) Innate immunity in the lungs. P Am Thorac Soc 2: 403–411. doi: 10.1513/pats.200508-090JS
    [81] Rasimus-Sahari S, Teplova VV, Andersson MA, et al. (2015) The peptide toxin amylosin of Bacillus amyloliquefaciens from moisture-damaged buildings is immunotoxic, induces potassium efflux from mammalian cells, and has antimicrobial activity. Appl Environ Microb 81: 2939–2949. doi: 10.1128/AEM.03430-14
    [82] van de Veerdonk FL, Gresnigt MS, Romani L, et al. (2017) Aspergillus fumigatus morphology and dynamic host interactions. Nat Rev Microbiol 15: 661–674. doi: 10.1038/nrmicro.2017.90
    [83] Kankkunen P, Rintahaka J, Aalto A, et al. (2009) Trichothecene mycotoxins activate inflammatory response in human macrophages. J Immunol 182: 6418–6425. doi: 10.4049/jimmunol.0803309
    [84] Peltonen S, Kari O, Jarva H, et al. (2008) Complement activation in tear fluid during occupational mold challenge. Ocul Immunol Inflamm 16: 224–229. doi: 10.1080/09273940802283323
    [85] Lam K, Schleimer R, Kern RC (2015) The etiology and pathogenesis of chronic rhinosinusitis: A review of current hypotheses. Curr Allergy Asthma Rep 15: 41. doi: 10.1007/s11882-015-0540-2
    [86] Veldhoen M (2017) Interleukin 17 is a chief orchestrator of immunity. Nat Immunol 18: 612–621. doi: 10.1038/ni.3742
    [87] Lichtenstein JHR, Hsu YI, Gavin IM, et al. (2015) Environmental mold and mycotoxin exposures elicit specific cytocine and chemocine responses. PLoS One 10: e0126926. doi: 10.1371/journal.pone.0126926
    [88] Nikulin M, Reijula K, Jarvis BB, et al. (1997) Effects of intranasal exposure to spores of Stachybotrys atria in mice. Fund Appl Toxicol 35: 182–188. doi: 10.1006/faat.1996.2274
    [89] Leino M, Mäkelä M, Reijula K, et al. (2003) Intranasal exposure to a damp building mould, Stachybotrys chartum, induces lung inflammation in mice by satratoxin-indipendent mechanisms. Clin Exp Allergy 33: 1603–1610. doi: 10.1046/j.1365-2222.2003.01808.x
    [90] King J, Richardson M, Quinn AM, et al. (2017) Bagpipe lung; a new type of interstitial lung disease? Thorax 72: 380–382. doi: 10.1136/thoraxjnl-2016-208751
    [91] Wolff H, Mussalo-Rauhamaa H, Raitio H, et al. (2009) Patients referred to an indoor air health clinic: Exposure to water-damaged buildings causes an increase of lymphocytes in bronchoalveolar lavage and a decrease of CD19 leucocytes in peripheral blood. Scand J Clin Lab Inv 69: 537–544. doi: 10.1080/00365510902770061
    [92] Tuuminen T, Lohi J (2018) Revising the criteria for occupational mold-related disease: Arguments, misconceptions and facts. EMJ Allergy Immunol 1: 128–135.
  • This article has been cited by:

    1. Talal Alzahrani, Raluca Eftimie, Dumitru Trucu, Multiscale moving boundary modelling of cancer interactions with a fusogenic oncolytic virus: The impact of syncytia dynamics, 2020, 323, 00255564, 108296, 10.1016/j.mbs.2019.108296
    2. Talal Alzahrani, Raluca Eftimie, Dumitru Trucu, Multiscale modelling of cancer response to oncolytic viral therapy, 2019, 310, 00255564, 76, 10.1016/j.mbs.2018.12.018
    3. Teekam Singh, Sandip Banerjee, Spatiotemporal dynamics of immunogenic tumors, 2020, 13, 1793-5245, 2050044, 10.1142/S1793524520500448
    4. Johannes P. W. Heidbuechel, Daniel Abate-Daga, Christine E. Engeland, Heiko Enderling, 2020, Chapter 21, 978-1-4939-9793-0, 307, 10.1007/978-1-4939-9794-7_21
    5. A. Diouf, H. Mokrani, D. Ngom, M. Haque, B.I. Camara, Detection and computation of high codimension bifurcations in diffuse predator–prey systems, 2019, 516, 03784371, 402, 10.1016/j.physa.2018.10.027
    6. Urszula Ledzewicz, Behrooz Amini, Heinz Schättler, Dynamics and control of a mathematical model for metronomic chemotherapy, 2015, 12, 1551-0018, 1257, 10.3934/mbe.2015.12.1257
    7. Dominik Wodarz, Computational modeling approaches to the dynamics of oncolytic viruses, 2016, 8, 19395094, 242, 10.1002/wsbm.1332
    8. YOUSHAN TAO, MICHAEL WINKLER, A critical virus production rate for efficiency of oncolytic virotherapy, 2021, 32, 0956-7925, 301, 10.1017/S0956792520000133
    9. Subhas Khajanchi, Sandip Banerjee, Influence of multiple delays in brain tumor and immune system interaction with T11 target structure as a potent stimulator, 2018, 302, 00255564, 116, 10.1016/j.mbs.2018.06.001
    10. Abdulhamed Alsisi, Raluca Eftimie, Dumitru Trucu, Non-local multiscale approach for the impact of go or grow hypothesis on tumour-viruses interactions, 2021, 18, 1551-0018, 5252, 10.3934/mbe.2021267
    11. B. I. Camara, H. Mokrani, A. Diouf, I. Sané, A. S. Diallo, Stochastic model analysis of cancer oncolytic virus therapy: estimation of the extinction mean times and their probabilities, 2022, 107, 0924-090X, 2819, 10.1007/s11071-021-07074-y
    12. H. Lefraich, 2022, Chapter 16, 978-3-031-12514-0, 287, 10.1007/978-3-031-12515-7_16
    13. Subhas Khajanchi, Juan J. Nieto, Spatiotemporal dynamics of a glioma immune interaction model, 2021, 11, 2045-2322, 10.1038/s41598-021-00985-1
    14. Pantea Pooladvand, Peter S. Kim, Modelling oncolytic virus diffusion in collagen-dense tumours, 2022, 2, 2674-0702, 10.3389/fsysb.2022.903512
    15. Abdulhamed Alsisi, Raluca Eftimie, Dumitru Trucu, Nonlocal multiscale modelling of tumour-oncolytic viruses interactions within a heterogeneous fibrous/non-fibrous extracellular matrix, 2022, 19, 1551-0018, 6157, 10.3934/mbe.2022288
    16. M. Kabong Nono, E.B. Megam Ngouonkadi, S. Bowong, H.B. Fotsin, Spatiotemporal dynamics and optimal control of glioma virotherapy enhanced by MEK Inhibitors, 2022, 7, 26667207, 100101, 10.1016/j.rico.2022.100101
    17. Iordanka Panayotova, Maila Hallare, 2023, Chapter 23, 978-3-031-21483-7, 247, 10.1007/978-3-031-21484-4_23
    18. Deivasundari P, M Kabong Nono, E B Megam Ngouonkadi, H B Fotsin, Anitha Karthikeyan, Bistability and chaotic behaviors in a 4D cancer oncolytic Virotherapy mathematical model: Pspice and FPGA implementations, 2024, 99, 0031-8949, 035227, 10.1088/1402-4896/ad25cb
    19. Arwa Abdulla Baabdulla, Thomas Hillen, Oscillations in a Spatial Oncolytic Virus Model, 2024, 86, 0092-8240, 10.1007/s11538-024-01322-z
    20. Dayong Qi, Xueyan Tao, Jiashan Zheng, Boundedness of the solution to a higher-dimensional triply haptotactic cross-diffusion system modeling oncolytic virotherapy, 2025, 25, 1424-3199, 10.1007/s00028-024-01040-y
  • Reader Comments
  • © 2018 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(11381) PDF downloads(2109) Cited by(8)

Article outline

Other Articles By Authors

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog