Viral Mimetic-Induced Inflammation Abolishes Q-Pathway, but Not S-Pathway, Respiratory Motor Plasticity in Adult Rats

• Main Authors: Austin D. Hocker, Adrianne G. Huxtable
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-08-01
• Series: Frontiers in Physiology
• Subjects: respiratory motor plasticity; viral inflammation; polyIC; inflammation; phrenic long-term facilitation
• Online Access: https://www.frontiersin.org/article/10.3389/fphys.2019.01039/full

Inflammation arises from diverse stimuli eliciting distinct inflammatory profiles, yet little is known about the effects of different inflammatory stimuli on respiratory motor plasticity. Respiratory motor plasticity is a key feature of the neural control of breathing and commonly studied in the form of phrenic long-term facilitation (pLTF). At least two distinct pathways can evoke pLTF with differential sensitivities to bacterial-induced inflammation. The Q-pathway is abolished by bacterial-induced inflammation, while the S-pathway is inflammation-resistant. Since viral-induced inflammation is common and elicits distinct temporal inflammatory gene profiles compared to bacterial inflammation, we tested the hypothesis that inflammation induced by a viral mimetic (polyinosinic:polycytidylic acid, polyIC) would abolish Q-pathway-evoked pLTF, but not S-pathway-evoked pLTF. Further, we hypothesized Q-pathway impairment would occur later relative to bacterial-induced inflammation. PolyIC (750 μg/kg, i.p.) transiently increased inflammatory genes in the cervical spinal cord (3 h), but did not alter medullary and splenic inflammatory gene expression, suggesting region specific inflammation after polyIC. Dose-response experiments revealed 750 μg/kg polyIC (i.p.) was sufficient to abolish Q-pathway-evoked pLTF at 24 h (17 ± 15% change from baseline, n = 5, p > 0.05). However, polyIC (750 μg/kg, i.p.) at 3 h was not sufficient to abolish Q-pathway-evoked pLTF (67 ± 21%, n = 5, p < 0.0001), suggesting a unique temporal impairment of pLTF after viral-mimetic-induced systemic inflammation. A non-steroidal anti-inflammatory (ketoprofen, 12.5 mg/kg, i.p., 3 h) restored Q-pathway-evoked pLTF (64 ± 24%, n = 5, p < 0.0001), confirming the role of inflammatory signaling in pLTF impairment. On the contrary, S-pathway-evoked pLTF was unaffected by polyIC-induced inflammation (750 μg/kg, i.p., 24 h; 72 ± 25%, n = 5, p < 0.0001) and was not different from saline controls (65 ± 32%, n = 4, p = 0.6291). Thus, the inflammatory-impairment of Q-pathway-evoked pLTF is generalizable between distinct inflammatory stimuli, but differs temporally. On the contrary, S-pathway-evoked pLTF is inflammation-resistant. Therefore, in situations where respiratory motor plasticity may be used as a tool to improve motor function, strategies targeting S-pathway-evoked plasticity may facilitate therapeutic outcomes.