Systemic inflammation impairs respiratory chemoreflexes and plasticity

Denne studien beskriver hvordan systemisk betennelse påvirker pustefunksjonen og gjør at det blir vanskeligere å endre pustemønser, f.eks. å gjøre pusteøvelser, eller å tilpasse pusten til aktivitetsnivå. Spesielt den kjemiske og motoriske delen av pustefysiologien blir dårligere. Noe som viser seg i laver CO2 sensitivitet (kjemisk) og svakere pustemuskler (Motorisk).

Nevner spesielt at det er mikroglia celler i CNS som påvirkes av betennelse, og som kan oppretthodle betennelse siden de sender ut cytokiner, m.m. Astrosytter kan også bidra mye siden de aktiverer NFkB. Den gode nyheten her er at økt CO2 nedregulerer NFkB. TLR-4 (Toll-like receptor) aktiveres av patogener og problemer i cellene, og aktiverer NFkB, og nedreguleres av økt CO2.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172820/

Abstract

Many lung and central nervous system disorders require robust and appropriate physiological responses to assure adequate breathing. Factors undermining the efficacy of ventilatory control will diminish the ability to compensate for pathology, threatening life itself. Although most of these same disorders are associated with systemic and/or neuroinflammation, and inflammation affects neural function, we are only beginning to understand interactions between inflammation and any aspect of ventilatory control (e.g. sensory receptors, rhythm generation, chemoreflexes, plasticity). Here we review available evidence, and present limited new data suggesting that systemic (or neural) inflammation impairs two key elements of ventilatory control: chemoreflexes and respiratory motor (vs. sensory) plasticity. Achieving an understanding of mechanisms whereby inflammation undermines ventilatory control is fundamental since inflammation may diminish the capacity for natural, compensatory responses during pathological states, and the ability to harness respiratory plasticity as a therapeutic strategy in the treatment of devastating breathing disorders, such as during cervical spinal injury or motor neuron disease.

Most lung and CNS disorders are associated with systemic and/or neural inflammation, including chronic lung diseases (Stockley, 2009), traumatic, ischemic and degenerative neural disorders (Teeling and Perry, 2009) and obstructive sleep apnea.

Systemic inflammation affects sensory receptors that modulate breathing, but can also trigger inflammatory responses in the central nervous system (CNS) through complex mechanisms. The primary CNS cells affected during systemic inflammation are microglia, the resident immune cells of the CNS, and astrocytes (Lehnardt, 2010).

Even when in their “resting state,” microglia are highly active, surveying their environment (Raivich, 2005,Parkhurst and Gan, 2010). When confronted with pathological conditions, such as neuronal injury/degeneration or bacterial/viral/fungal infection, they become “activated,” shifting from a stellate, ramified phenotype to an amoeboid shape (Kreutzberg, 1996). Activated microglia can be phagocytic, or they can release toxic and protective factors, including cytokines, prostaglandins, nitric oxide or neurotrophic factors (e.g. BDNF) (Kreutzberg, 1996Graeber, 2010). Despite the importance of microglia in immune function, they are diffuse in the CNS (~70-90% of CNS cells are glia; microglia are ~5-10% of those cells).

Astrocytes, on the other hand, contribute to the overall inflammatory response since they release cytokines, triggering nuclear factor-kappa B (NFκB) signaling elsewhere in the CNS. Further, they express many TLRs, including TLR-4, capable of eliciting an inflammatory response (Li and Stark, 2002Farina et al., 2007,Johann et al., 2008). Given their relative abundance, astrocytes may play a key role in CNS inflammatory responses.

TLR-4 receptors are cytokine family receptors that activate transcription factors, such as NFκB (Lu et al., 2008). NFκB regulates the expression of many inflammatory genes, including: IL-1β, -6 and -18, TNFα, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) (Ricciardolo et al., 2004Nam, 2006). Endogenous molecules known to activate TLR-4 receptors include (but are not limited to) heat shock proteins (specifically HSP60, Ohashi et al., 2000Lehnardt et al., 2008), fibrinogen, surfactant protein-A, fibronectin extra domain A, heparin sulfate, soluble hyaluronan, β-defensin 2 and HMGB1 (Chen et al., 2007).

The role of inflammation (and specifically microglia) in chronic pain has been studied extensively (reviewed in Woolf and Salter, 2000Trang et al., 2006Mika, 2008Abbadie et al., 2009Baumbauer et al., 2009). A remarkable story has emerged, demonstrating the interplay between neurons, microglia, inflammation and plasticity in this spinal sensory system. In short, inflammation induces both peripheral and central sensitization, leading to allodynia (hypersensitivity to otherwise non-painful stimuli) and hyperalgesia (exaggerated or prolonged responses to a noxious stimulus) (Mika, 2008).

An important aspect of ventilatory control susceptible to inflammatory modulation is the chemoreflex control of breathing. Chemoreflexes are critical for maintaining homeostasis of arterial blood gases viaclassical negative feedback (Mitchell et al., 2009), or acting as “teachers” that induce plasticity in the respiratory control system (Mitchell and Johnson, 2003). Major chemoreflexes include the hypoxic (Powell et al., 1998) and hypercapnic ventilatory responses (Nattie, 2001), arising predominantly from the peripheral arterial and central chemoreceptors (Lahiri and Forster, 2003).

To date, no studies have reported the impact of systemic inflammation on hypercapnic responses. However, increased CO2 suppresses NFκB activation, possibly suppressing inflammatory gene expression (Taylor and Cummins, 2011). In fact, hypercapnia has been used to treat ischemia/reperfusion injury to decrease inflammation and reduce lung tissue damage (Laffey et al., 2000O’Croinin et al., 2005Curley et al., 2010Li et al., 2010).

Further work concerning the influence of systemic inflammation on hypercapnic ventilatory responses is warranted, particularly since impaired CO2 chemoreflexes would allow greater hypercapnia and minimize the ongoing inflammation; in this sense, impaired hypercapnic ventilatory responses during inflammation may (in part) be adaptive.

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