A major implication of diminished chemoreflexes and respiratory plasticity with systemic inflammation is that, at a time when robust ventilatory control is needed the most (i.e. disease), the neural system controlling breathing may be compromised. A major goal should be to understand the extent and mechanisms compromising this critical homeostatic control system.
Although information is now becoming available concerning the impact of acute inflammation (<24 hrs) on ventilatory control, future investigations must explore longer time-domains. Longer time-domains are characteristic of chronic lung and neural diseases (Iturriaga et al., 2009
, Del Rio et al., 2010
). Further, inflammation is a dynamic process; specific combinations of inflammatory molecules expressed at any given time differ. Thus, it is not clear that acute and chronic inflammation will have the same impact on ventilatory control.
Here, we reviewed evidence that systemic inflammation activates brainstem and spinal inflammatory responses, impairing chemoreflexes and respiratory plasticity. However, most available evidence concerns exogenously induced models of inflammation, such as systemic LPS. Further research is necessary to confirm that this model reveals general principles applicable to endogenous inflammation characteristic of chronic lung disease (e.g. COPD), breathing disorders (e.g. sleep apnea) and neurological disorders, including traumatic, ischemic and neurodegenerative processes.
Sleep apnea and the attendant chronic intermittent hypoxia induce CNS inflammation and impair cognitive function (Gozal, 2009
, McNicholas, 2009
, Ryan et al., 2009
, Inancli and Enoz, 2010
, Kimoff et al., 2010
). If chronic intermittent hypoxia-induced inflammation alters respiratory chemoreflexes and plasticity, then disease/ventilatory control interactions may contribute to the underlying pathophysiology. For example inflammation induced by sleep-disordered breathing may undermine spontaneous respiratory compensation, exacerbating the primary breathing disorder. Research concerning this possibility seems warranted.
In recent years, we have started to harness respiratory plasticity as a treatment for conditions associated with respiratory insufficiency, such as cervical spinal injury (Mitchell, 2007
; Vinit et al., 2009
). Inherent in these disorders is an element of (endogenous) inflammation, characterized by increased expression of pro- and anti-inflammatory molecules (Lehnardt, 2010
). Patients with respiratory insufficiency are prone to greater rates of infection and generalized immune activation (Wills-Karp, 1999
, Stockley, 2009
, Oglesby et al., 2010
). Because of the high incidence of inflammatory activity in respiratory disorders, a major obstacle in harnessing respiratory plasticity as a therapeutic tool may be overcoming the limits imposed by inflammation. Thus, therapeutic induction of respiratory (or other motor) plasticity may be optimized if the patients are first given anti-inflammatory agents. Before such combinatorial therapies can/should be applied, we need more information regarding mechanisms whereby inflammation impairs the neural control of breathing.
Overall, the theme of this special edition is quite novel in the context of respiratory neurobiology. We are only now beginning to appreciate the impact of inflammation on neural function in other regions of the nervous system (Di Filippo et al., 2008
, Abbadie et al., 2009
, Iturriaga et al., 2009
). Although many human clinical conditions that require rigorous ventilatory control to assure adequate breathing are associated with inflammation, we are only at the beginning of our understanding concerning how inflammation impacts neural mechanisms that underlie any aspect of ventilatory control (e.g. rhythm generation, chemoreflexes, plasticity). We should move quickly to understand the impact of this common biological event (i.e. inflammation) on respiratory control.