Hydrogen sulfide alleviates hyperoxia effects on mitochondria in human developing airway smooth muscle
Colleen M. Bartman, Michael Thompson, Samantha K. Hamrick, Niyati A. Borkar, Daniel Pfeffer-Kleemann, Preetham Ravi, Marta Schiliro, Yak Nak, Christian Vivar Ramon, Li Drake, Y.S. Prakash, Christina Pabelick
Colleen M. Bartman, Michael Thompson, Samantha K. Hamrick, Niyati A. Borkar, Daniel Pfeffer-Kleemann, Preetham Ravi, Marta Schiliro, Yak Nak, Christian Vivar Ramon, Li Drake, Y.S. Prakash, Christina Pabelick
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Research Article Cell biology Pulmonology Therapeutics

Hydrogen sulfide alleviates hyperoxia effects on mitochondria in human developing airway smooth muscle

Abstract

Moderate hyperoxia (30%–60% O2) in premature infants promotes bronchial airway hyperresponsiveness (AHR) via airway smooth muscle (ASM), a key regulator of bronchoconstriction, bronchodilation, and remodeling. Understanding how O2 exposure drives long-term bronchial changes in prematurity is critical for developing therapies for airway disease across the lifespan. Premature lungs have immature antioxidant defenses, potentially due to disrupted mitochondrial dynamics, increasing susceptibility to O2-induced oxidative stress. Thus, mitochondrial homeostasis is highly relevant to ASM dysfunction and airway disease. We propose that hyperoxia in prematurity promotes mitochondrial dysfunction, and that the gasotransmitter hydrogen sulfide (H2S) mitigates O2-induced mitochondrial damage in developing ASM. Human fetal ASM (fASM) cells were exposed to moderate hyperoxia to investigate the effects of exogenous H2S donors (GYY4137, AP39) and stabilization of cystathionine β-synthase (CBS), an H2S biosynthetic enzyme, on mitochondrial structure and function. Hyperoxia impaired fASM cell mitochondrial integrity, while H2S donors in particular, or CBS stabilization attenuated adverse O2 effects on mitochondrial morphology, ROS, respiration, calcium regulation, and contractility. These findings highlight the therapeutic potential of H2S in the premature lung exposed to moderate hyperoxia.

Authors

Colleen M. Bartman, Michael Thompson, Samantha K. Hamrick, Niyati A. Borkar, Daniel Pfeffer-Kleemann, Preetham Ravi, Marta Schiliro, Yak Nak, Christian Vivar Ramon, Li Drake, Y.S. Prakash, Christina Pabelick

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Figure 7

H2S attenuates O2 effects on calcium through the cAMP pathway.

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H2S attenuates O2 effects on calcium through the cAMP pathway. (A and B)...
(A and B) fASM cells were treated as follows: vehicle in 21% O2, vehicle in 40% O2, 50 µm GYY4137 in 40% O2, 50 µm GYY4137 + 100 nM KT5720 (PKA inhibitor) in 40% O2, or 50 µm GYY4137 + 10 µm SQ22536 (AC inhibitor) in 40% O2. (A) Cells were loaded with 5 µm Fura-2/AM for live cell fluorescent imaging of [Ca2+]c response to 10 µm histamine. Amplitude [Ca2+]c responses were calculated as in Figure 3C. Representative tracings (1 of 6) are shown. (B) Cells were loaded with 1 µm Rhod-2 for live cell fluorescent imaging of [Ca2+]m response to 10 µm histamine. [Ca2+]m response was calculated as in Figure 3D. Representative tracings are shown (1 of 5). (C) fASM cells were treated as follows: vehicle in 21% O2, vehicle in 40% O2, 100 nM AP39 in 40% O2, 100 nM AP39 + 100 nM KT5720 in 40% O2, or 100 nM AP39 + 10 µm SQ22536 in 40% O2. Cells were loaded with 1 µm Rhod-2 for live cell fluorescent imaging of [Ca2+]m response to 10 µm histamine. Representative tracings are shown (1 of 5). ##P < 0.01; ###P < 0.001 by unpaired t test; *P < 0.05; **P < 0.01; ***P < 0.001 by 2-way ANOVA with Bonferroni’s correction for multiple comparisons. Data are represented as mean ± SEM; n = 5–6 fASM lines/group.