Molecular pathway of near-infrared laser phototoxicity involves ATF-4 orchestrated ER stress

Abstract

High power lasers are used extensively in medicine while lower power applications are popular for optical imaging, optogenetics, skin rejuvenation and a therapeutic modality termed photobiomodulation (PBM). This study addresses the therapeutic dose limits, biological safety and molecular pathway of near-infrared (NIR) laser phototoxicity. Increased erythema and tissue damage were noted in mice skin and cytotoxicity in cell cultures at phototoxic laser doses involving generation of reactive oxygen species (ROS) coupled with a rise in surface temperature (>45 °C). NIR laser phototoxicity results from Activating Transcription Factor-4 (ATF-4) mediated endoplasmic reticulum stress and autophagy. Neutralizations of heat or ROS and overexpressing ATF-4 were noted to rescue NIR laser phototoxicity. Further, NIR laser mediated phototoxicity was noted to be non-genotoxic and non-mutagenic. This study outlines the mechanism of NIR laser phototoxicity and the utility of monitoring surface temperature and ATF4 expression as potential biomarkers to develop safe and effective clinical applications.

Biological effects of Er:YAG laser irradiation on the proliferation of primary human gingival fibroblasts

“…The HSP70 family proteins encoded by these genes are conserved molecular chaperones essential for proper folding and assembly of proteins. They are important for protecting cells from damage caused by a variety of stressors , including hyperthermia . In particular, HSPA6 is induced only at high temperature and shows little or no basal expression .…”

Photobiomodulation Therapy Promotes Expansion of Epithelial Colony Forming Units

“…7 However, higher doses of the NIR laser induce phototoxicity by generating excessive ROS and heat, resulting in prominent unfolded protein response and endoplasmic reticulum stress leading to excessive autophagy, apoptosis, and tissue damage. 13 These responses indicate the critical importance of clinical dosing for PBM treatments where the therapeutic biological responses can be optimally harnessed for clinical therapy.…”

“…13,15 This study first established a therapeutic dose that had a distinct beneficial effect on epithelial stem cells' CFU and observed that a low level of light energy is beneficial while higher levels are detrimental. These observations highlight the importance of dose with PBM therapy that follows the Arendt-Schultz curve supporting hormetic responses with radiant energy delivery.…”

“…The physical parameters of these devices include the source (coherence and collimation), peak wavelength, dose (irradiance, time, and fluence), among others, need to be optimized to ascertain therapeutic effects, while concurrently avoiding detrimental phototoxicity. 13 In this study, two keratinocyte cell lines were used from the skin and mucosa. Colony formation assay was used to assess expansion (increase in number) of epithelial stem cells following light treatment.…”

Photobiomodulation leads to enhanced radiosensitivity through induction of apoptosis and autophagy in human cervical cancer cells

“…Therefore, persistence of γ-H2AX indicates impaired DNA repair. Khan et al (2015) examined γ-H2AX after laser irradiation [41]. They did not find any evidence for non-repaired DSBs after laser irradiation.…”