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1. 13/12/2011
Semi -Quantitative Assessment of Inducible NO Synthase in an Acute Inflammation Model
Yumi Moriyama1, Jamie Fong 2 , Arkady Mandel 2 , Margarete K. Akens 3 , Lothar Lilge 1,4
1 Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada, 2 Theralase Inc. Toronto, Canada, 3 Sunnybrook and Women’s College Health Centre., Toronto, Canada 4 Medical Biophysics, University of Toronto, Toronto, Canada
Abstract: Methodology TABLE. Comparison of Sum of Integral of BLI as a Function of
Results
While various mechanisms of action for Low Level Ages in Different LLLT Exposures
Laser Therapy have been proposed, it is evident that 30 transgenic iNOS-luc ( FVB/N-Tg) mice Control
the photon energy delivered to the tissue is (n=10) and Treated (n=30) startified as young < Histological analysis (l=635nm) Groups < 15 week 15-32 weeks > 1year P-value
insufficient as an energy source for any biological 15 weeks versus old > 1 year.
outcome and needs to be augmented by biological Control 9.97 – 3.7 5.65 – 4.7 3.42-1.43 0.021*
processes to improve ATP production or similar. M 635 1.57 – 3.9 3.28 – 4.3 15.2-8.9 0.02*
While in the short, high quantum energy range of F 660 2.88 – 4.9 5.18 – 5.6 0.290
T
LLLT, direct photochemical activation is feasible,
Luciferase Gene From
American Firefly P. Pyrallis 690 2.70 – 4.0 1.44 – 2.4 0.03*
energies at longer NIR wavelengths are typically 785 4.4 -4.2 0.64
insufficient for the majority of photochemical •luciferin + ATP → luciferyl adenylate + PPi 808 3.62-1.2 0.84
PBS [5h] No-LLLT [5h] LLLT [5h]
processes. However, other photophysical processes 905 CW 3.66 – 5.15 6.15 – 3.1 9.21-2.84 0.745
Semi-quantifiable differences in the macrophages and other invading
can lead to activation of the immune system, even by •luciferyl adenylate + O2 → oxyluciferin + AMP + LIGHT cell within the synovial space are evident with more cells seen for 905 PW 15.45 – 5.1 6.61 – 4.1 0.021*
short, transient, thermal effects. Monitoring immune reduced iNOS BLI signal and late time to maximum BLI counts.
modulation effects due to LLLT can become a very Injection of Zymosan A: (yeast cell wall) in PBS P values considered statistically significant are represented
powerful method to understand underlying 12000
with asterisk (*).
mechanisms. NO is a powerful modulator for the Laser irradiation: control
immune system and inducible NO synthase (iNOs) a 10000 635 Discussion
15 min after injection
BLI counts[photons/sec]
785
direct surrogate for its activity. Exploiting Wavelengths: 635nm (n=5) 8000 808
bioluminescence when the luciferase gene is placed 905 Laser therapy 15 minutes post- induction of inflammation
660nm (n=5) 6000
resulted in less recruitment of inflammatory cells to the site,
within the promoter region of iNOs permits the
temporal monitoring of iNOs expression. In an acute
785nm (n=4) 4000 possibly by altering the mechanism of cell attachment by NO
model of inflammation in the murine knee joint it 808nm (n=5)
2000
was shown that a single treatment of 50mW/cm2 905nm (n=11) LLLT increased the expression of iNOS per cell with particular
irradiance of a pulsed NIR light (905nm, 200nsec), 0 PW 905 also showing an earlier time to peak (~5 hrs)
0 5 10 15 20 25 30
with 14mW power and 5J/cm2 radiant exposure, Irradiance: 50 mW cm-2 time[h]
(0.28cm2 spot size), low duty cycle, was most LLLT of 635nm leads to upregulation of iNOS expression, in
radiant power: 5J cm-2 young animals but not as effectively as the longer wavelengths
effective in modulating iNOs expression, showing a iNOS related BLI signal as function of time post Zymosan A
rapid onset. Histology showed an inverse correlation administration for a subset of mice. Average and stdev for n=4, young It seems that iNOS expression is playing a role in the anti-
mice at , 15 weeks only. (from Moriyama Y. et. al. Photochem.
of inflammatory cell concentration in the synovium Photobiol. 2005, 81:1351-1365
inflammatory mechanisms of LLLT.
and integrated bioluminescence signal over the first Longer wavelength appear more effective in older animals.
24hrs of inflammation induction. These results
suggest that high iNOs expression may play a critical
role in the anti-inflammatory mechanisms of LLLT
expression post inflammation may prevent
conversion of an acute inflammation into a chronic
one.
Luciferin injected and bioluminescence images Limitations
See also: Moriyama, Y., Nguyen, J., Akens, M., acquired
The study was executed over multiple years with various students
Moriyama, E., Lilge, L. 2009. Lasers in Surgery and an technical staff performing the breading and genotyping and the
Medicine. 41:227-231. experiments. Variability in determination of homozygous versus
heterozygous state are small, however, success rates in Zymosan
A and Luciferin administration can not be excluded. Unfortunately
we could not randomize the treatment protocols over the
Action spectra of LLLT on iNOS BLI signal. Solid symbols: animals <15 duration of these experiments. The number N of animals is still
weeks. Open symbols: animals >15 weeks so younger than 8 months. low.
Gray symbols: data from Ref. [13], with experiments executed in mice
older than 1 year (signal corrected for homozygote vs. heterozygote
used here). Triangles (~) refer to 905 nm in pulsed wave (PW) mode.
Standard deviations are listed in Table I.
Acknowledgement
The authors with to express their gratitude to Drs. E. Moriyama, R.
t=0h t=3h t=5h t=7h t=9h t=24h Weersink, and Miss J. Nguyen for their support of these studies.
Funding was provided by Ontario Centres of Excellence, Photonics
Research Ontario and Theralase Inc.
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