The impact of inflammation on respiratory plasticity

Abstract

Breathing is a vital homeostatic behavior and must be precisely regulated throughout life. Clinical conditions commonly associated with inflammation, undermine respiratory function may involve plasticity in respiratory control circuits to compensate and maintain adequate ventilation. Alternatively, other clinical conditions may evoke maladaptive plasticity. Yet, we have only recently begun to understand the effects of inflammation on respiratory plasticity. Here, we review some of common models used to investigate the effects of inflammation and discuss the impact of inflammation on nociception, chemosensory plasticity, medullary respiratory centers, motor plasticity in motor neurons and respiratory frequency, and adaptation to high altitude. We provide new data suggesting glial cells contribute to CNS inflammatory gene expression after 24h of sustained hypoxia and inflammation induced by 8h of intermittent hypoxia inhibits long-term facilitation of respiratory frequency. We also discuss how inflammation can have opposite effects on the capacity for plasticity, whereby it is necessary for increases in the hypoxic ventilatory response with sustained hypoxia, but inhibits phrenic long term facilitation after intermittent hypoxia. This review highlights gaps in our knowledge about the effects of inflammation on respiratory control (development, age, and sex differences). In summary, data to date suggest plasticity can be either adaptive or maladaptive and understanding how inflammation alters the respiratory system is crucial for development of better therapeutic interventions to promote breathing and for utilization of plasticity as a clinical treatment.

Keywords: Acclimatization; Hypoxia; Inflammation; Motor plasticity; Neuroplasticity; Respiratory plasticity; Sensory plasticity.

Figure 1

Systemic minocycline administration inhibits cytokine gene expression in the NTS following 24 hours of CSH. Three groups of rats (n=5/group) were exposed to one of the following conditions: 1) Normoxic (controls); 2) 24-hour CSH (10% O₂) + i.p. saline; or, 3) 24-hour CSH (10% O₂) + i.p. minocycline (45mg/kg). RT-PCR was used to assess cytokine mRNA in the NTS region of the rat brainstem. Exposure to 24-hours of CSH increased both IL-6 and TNF-α mRNA compared to normoxic controls. Systemic minocycline administration blocked the IL-6 and TNF-α mRNA increase. All data presented as mean ± SEM. Two-way ANOVA, Bonferroni post-test; p < 0.05; * indicates difference between normoxia and 24-hour Hypoxia + Saline; # indicates difference between 24-hour Hypoxia + Saline and 24-hour Hypoxia + Minocycline.

Figure 2

Frequency plasticity is blunted by IH-1 and is restored after spinal treatment with a p38 MAPK inhibitor (SB202190, 1 mM, intrathecal). A) Phrenic nerve frequency responses during the short-term hypoxic response were not altered by IH-1 or intrathecal p38 inhibition. B) Frequency plasticity was evident in normoxia controls (n = 9) and was not altered by p38 inhibition (n = 7). Frequency plasticity was eliminated by IH-1 (n = 6), but was restored after p38 MAPK inhibition (n = 7). Time controls with intrathecal vehicle application (n = 7) did show increased phrenic frequency after 90 minutes relative to baseline, which was absent after the p38 inhibitor (n=5). (Two-way RM ANOVA, Fisher LSD post-test; # indicates difference from baseline, * indicates difference from p38 time controls, † indicates difference from normoxia vehicle controls.)

Figure 3

Models of inflammation and effects on plasticity. Multiple models of inflammation converge on pro-inflammatory pathways that alter the expression of plasticity in respiratory and non-respiratory systems.