title: Adenosine-dependent phrenic motor facilitation is inflammation resistant.
abstract: Phrenic motor facilitation (pMF), a form of respiratory plasticity, can be elicited by acute intermittent hypoxia (i.e., phrenic long-term facilitation, pLTF) or direct application of drugs to the cervical spinal cord. Moderate acute intermittent hypoxia (mAIH; 3 × 5-min episodes of 35-50 mmHg arterial Po2, 5-min normoxic intervals) induces pLTF by a serotonin-dependent mechanism; mAIH-induced pLTF is abolished by mild systemic inflammation induced by a low dose of lipopolysaccharide (LPS; 100 μg/kg ip). In contrast, severe acute intermittent hypoxia (sAIH; 3 × 5-min episodes of 25-30 mmHg arterial Po2, 5-min normoxic intervals) elicits pLTF by a distinct, adenosine-dependent mechanism. Since it is not known if systemic LPS blocks the mechanism giving rise to sAIH-induced pLTF, we tested the hypothesis that sAIH-induced pLTF and adenosine 2A (A2A) receptor-induced pMF are insensitive to mild systemic inflammation elicited by the same low dose of LPS. In agreement with our hypothesis, neither sAIH-induced pLTF nor cervical intrathecal A2Areceptor agonist (CGS-21680; 200 μM, 10 μl × 3)-induced pMF were affected 24 h post-LPS. Pretreatment with intrathecal A2Areceptor antagonist injections (MSX-3; 10 μM, 12 μl) blocked sAIH-induced pLTF 24 h post LPS, confirming that pLTF was adenosine dependent. Our results give insights concerning the differential impact of systemic inflammation and the functional significance of multiple cascades capable of giving rise to phrenic motor plasticity. The relative resistance of adenosine-dependent pMF to inflammation suggests that it provides a "backup" system in animals lacking serotonin-dependent pMF due to ongoing inflammation associated with systemic infections and/or neural injury.NEW & NOTEWORTHYThis study gives novel insights concerning how a mild systemic inflammation impacts phrenic motor plasticity (pMF), particularly adenosine-dependent pMF. We suggest that since this adenosine-dependent pathway is insensitive to systemic inflammation, it represents an alternative or "backup" mechanism of pMF when other mechanisms are suppressed.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin; and.
authors.forename: Ibis M
authors.initials: IM
authors.lastname: Agosto-Marlin
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin; and.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Nichols
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin; and gsmitche@phhp.ufl.edu.|Center for Respiratory Research and Rehabilitation, Department of Physical Therapy and McKnight Brain Institute, University of Florida, Gainesville, Florida.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Mitchell
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000150:complications; D008070:Lipopolysaccharides / Q000633:toxicity; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D010791:Phrenic Nerve / Q000502:physiology*; D058905:Purinergic Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000209:etiology; D013997:Time Factors; D014970:Xanthines / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D008070:Lipopolysaccharides; C113602:MSX 3 compound; D010627:Phenethylamines; D058905:Purinergic Agents; D014970:Xanthines; C023023:lipid-linked oligosaccharides; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine
keywords: acute intermittent hypoxia; adenosine; inflammation; respiratory plasticity; spinal plasticity