Aquaporins and radiation(?)

In trying to find information on the effect of radiation on aquaporins, a paper came up on a treatment for radiation-induced salivary hypofunction:

Baum, Bruce J., Changyu Zheng, Ana P. Cotrim, Linda McCullagh, Corinne M. Goldsmith, Jaime S. Brahim, Jane C. Atkinson, et al. “Aquaporin-1 Gene Transfer to Correct Radiation-Induced Salivary Hypofunction.” Handbook of Experimental Pharmacology, no. 190 (2009): 403–18. https://doi.org/10.1007/978-3-540-79885-9_20.

        "Indeed, IR leads to a dramatic loss of the fluid secreting salivary acinar cells, resulting in severe glandular hypofunction (a diminished production of saliva) in most patients (Vissink et al. 2003; Nagler and Baum 2003). The reason for this damage remains enigmatic, as salivary acinar cells are well differentiated and very slowly dividing, the opposite of the classical target cell for IR sensitivity [emphasis added]. If patients have sufficient functional acinar tissue post-IR, it is possible to treat their salivary hypofunction with cholinergic drugs (Shiboski et al. 2007). However, most post-IR patients have salivary glands characterized by inadequate acinar cell mass with non-fluid secreting duct cells surviving and predominating (Vissink et al. 2003; Nagler and Baum 2003). There is no effective conventional therapy for these patients, a situation that led us to consider the use of gene therapy, i.e., in vivo gene transfer, as a therapeutic approach to repair damaged glands (Baum et al. 1999). The gene of choice was human aquaporin-1 (hAQP1).

        The specific strategy we adopted is depicted in Fig. 1. This strategy was based on the understanding of salivary fluid secretion and salivary duct cell physiology available in 1991 (Baum 1993). In this figure, a surviving duct cell in an IR-damaged salivary gland is illustrated. We hypothesized that it would be possible for this cell to secrete fluid through the transfer of a gene encoding a functional, non-polarized water channel protein. Our hypothesis included a view that the duct cells could generate an osmotic gradient, lumen > interstitium, in the absence of any significant acinar cell secretion and the expression of a water channel in these normally water impermeant cells would in turn permit osmotically driven transepithelial fluid flow into the lumen. The specific hypothesis, in brief, is as follows. In the absence of an isotonic acinar cell secretion, most of the membrane transport proteins then-known to be present in the duct cell luminal membrane would be inactive owing to the low luminal concentrations of their respective substrates; these include the epithelial sodium channel, the cystic fibrosis transmembrane conductance regulator (i.e., a chloride channel) and the sodium/proton exchanger. However, a potassium/proton exchanger in the luminal membrane would be active and able to exchange intracellular potassium for a proton that could be generated in the lumen from the dissolution of CO₂ in the small amount of diffused water that normally should be present. The CO₂ would dissociate to yield the exchangeable proton and HCO₃⁻, resulting in a KHCO₃ osmotic gradient. As shown, the cDNA for hAQP1 has been transferred and it assumes a non-polarized distribution all around the plasma membrane. Water then would be able to flow across the duct cell into the lumen in response to the hypothesized KHCO₃ gradient. It is important to recognize that this hypothetical mechanism is still unproven, but the gene transfer strategy, as is presented below, has been successfully utilized in small and large animal pre-clinical models."

What prompted the search for information on the effects of radiation was the finding that radiation therapy can improve outcomes in severe COVID-19 (references below) and of course I am wondering about the specifics of the mechanism of action. Presumably radiation induces a change in immune cell function -  but how, exactly, is the change mediated?

I suspect aquaporins may be involved. The role of aquaporins in inflammation is reviewed here:

Meli, Rosaria, Claudio Pirozzi, and Alessandra Pelagalli. “New Perspectives on the Potential Role of Aquaporins (AQPs) in the Physiology of Inflammation.” Frontiers in Physiology 9 (2018): 101. https://doi.org/10.3389/fphys.2018.00101.

        "Further data supports these findings showing that Th2 cytokines and IL-4, both involved in mucin gene expression, are down-regulated in AQP5 knockout mouse (Karras et al., 2007), thus suggesting the contribution of this channel protein in effective Th2-driven responses to allergens. More recently, the relationship between the AQP5 deletion and elevated IFN-α and IL-2 production was evidenced, indicating that this protein acts in the shift from Th2 toward Th1 response in a murine model of mucous hyperproduction during antigen-induced airway inflammation (Shen et al., 2011). It is well-known that Th2 cytokines operate in these pathologies with different mechanisms such as eosinophil recruitment, airway hyper-responsiveness and mucus hypersecretion (Tomkinson et al., 2001; Walter et al., 2001)"

 { This paper has a lot of references to papers by Medzhitov which I need to read ... }

No answer as yet, though, on what exactly radiation does to aquaporins ...

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References on COVID-19 radiation therapy:

Ameri, Ahmad, Nazanin Rahnama, Rama Bozorgmehr, Majid Mokhtari, Mohammad Farahbakhsh, Mahmood Nabavi, Simin Dokht Shoaei, et al. “Low-Dose Whole-Lung Irradiation for COVID-19 Pneumonia: Short Course Results.” International Journal of Radiation Oncology, Biology, Physics, July 21, 2020. https://doi.org/10.1016/j.ijrobp.2020.07.026.

“Low-Dose Whole-Lung Radiation for COVID-19 Pneumonia: Planned Day-7 Interim Analysis of a Registered Clinical Trial | MedRxiv.” Accessed August 2, 2020. https://www.medrxiv.org/content/10.1101/2020.06.03.20116988v1.

      

        It is interesting to note that 4 of the 5 patients in this trial were women and they experienced improvement. Studies of mice and flies have found radiation at low doses to be a hormetic effector, increasing lifesppan, but only in males. This sex difference in lifespan extension is also true for most 'geroprotectors' (e.g., acarbose is much more effective in males but has some efficacy for females [ https://youtu.be/YPzv0Ns7tJY ]). However, the mechanism of action may be different in radiation for life extension vs. immune function modulation (and the dosing is probably quite a bit different, but I don't have time to look it up and am not sure how to compare radiation dosing between mice and humans anyway).