Oleg Broytman

Anti-Aβ: The Good, the Bad, and the Unforeseen

Alzheimers disease (AD) is characterized in part by the deposition of amyloid β protein (Aβ) in compact fibrillar plaques. These structures can induce an innate immune response in the brain, which triggers progressive inflammation, neuronal loss, and further acceleration of Aβ plaque formation. Compared with the case in normal individuals, the T and B lymphocytes in AD patients and murine models are hyporesponsive to Aβ. However, depending on the route of delivery, tolerance can be overcome by vaccination, with the induction of an anti‐Aβ‐mediated immune response. Through mechanisms that are incompletely understood, immunized APP transgenic animals show markedly reduced Aβ deposition, preservation of normal neuronal architecture, and improved performance in memory and spatial learning tasks. In human trials, Aβ vaccination stabilized cognition and slowed the progression of dementia. Neuropathologic examination of a vaccinated subject showed reduced cortical Aβ without changes in other AD‐associated pathology. However, in some patients, vaccination induced severe meningoencephalitis, causing the trial to be terminated. Thus, vaccination appears to activate both beneficial and deleterious anti‐Aβ immunity, suggesting that the vaccine can have potent clinical utility if an appropriate immunologic response can be generated.

Obstructive Sleep Apnea Risk, Asthma Burden, and Lower Airway Inflammation in Adults in the Severe Asthma Research Program (SARP) II

BACKGROUND Obstructive sleep apnea (OSA) may worsen asthma, but large studies are lacking and the underlying mechanisms are unknown. OBJECTIVE The objective of this study was to determine the prevalence of OSA risk among patients with asthma of different severity compared with normal controls (NC), and among asthmatics, to test the relationship of OSA risk with asthma burden and airway inflammation. METHODS Subjects with severe (SA, n = 94) and nonsevere asthma (NSA, n = 161), and NC (n = 146) were recruited in an add-on substudy, to the observational Severe Asthma Research Program (SARP) II; subjects completed sleep quality, sleepiness and OSA risk (Sleep Apnea scale of the Sleep Disorders Questionnaire [SA-SDQ]) questionnaires, and clinical assessments. Sputum was induced in a subset of asthmatics. RESULTS Relative to NC, despite similar sleep duration, the subjects with SA and NSA had worse sleep quality, were sleepier, and had higher SA-SDQ scores. Among asthmatics, higher SA-SDQ was associated with increased asthma symptoms, β-agonist use, health care utilization, and worse asthma quality of life. A significant association of SA-SDQ with sputum polymorphonuclear cells% was noted: each increase in SA-SDQ by its standard deviation (6.85 units) was associated with a rise in % sputum neutrophils of 7.78 (95% CI 2.33-13.22, P = .0006), independent of obesity and other confounders. CONCLUSIONS OSA symptoms are more prevalent among asthmatics, in whom they are associated with higher disease burden. OSA risk is associated with a neutrophilic airway inflammation in asthma, which suggests that OSA may be an important contributor to the neutrophilic asthma. Further studies are necessary to confirm these findings and better understand the mechanistic underpinnings of this relationship.

Effects of Chronic Intermittent Hypoxia on Allergen-Induced Airway Inflammation in Rats

Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats. Four groups (n = 9-11/group) of ovalbumin (OVA)-sensitized Brown-Norway rats underwent intermittent hypoxia (10% oxygen, 30 cycles/h, 10 h/d) or normoxia for 30 days concurrent with weekly OVA or vehicle challenges. Lung physiology, differential leukocyte counts from bronchoalveolar lavage, and histology (Picro Sirius Red staining for collagen content) were compared between groups 2 days after the last challenge. Gene expression in bronchoalveolar lavage cells was quantified by quantitative PCR. Compared with normoxia, chronic intermittent hypoxia reduced the FEV0.1/FVC ratio (P = 0.005), peak expiratory flow (P = 0.002), and mean midexpiratory flow (P = 0.004), predominantly in medium and large airways; decreased the baseline eosinophil number (P = 0.01) and amplified the effect of OVA on monocyte number (P = 0.02 for the interaction); in proximal airways, increased (P = 0.008), whereas in distal airways it decreased (P = 0.004), collagen density; induced qualitative emphysematous changes in lung periphery; and increased expression of the M2 macrophage marker YM-1 and augmented OVA-induced expression of plasminogen activator inhibitor-1. Chronic intermittent hypoxia alters immune response to allergen toward a more TH-1-predominant cellular phenotype with collagen deposition and matrix degradation, leading to airflow limitation. These findings highlight the potential of sleep apnea to aggravate airway dysfunction in patients with preexistent asthma.

Spinal Atypical Protein Kinase C Activity Is Necessary to Stabilize Inactivity-Induced Phrenic Motor Facilitation

The neural network controlling breathing must establish rhythmic motor output at a level adequate to sustain life. Reduced respiratory neural activity elicits a novel form of plasticity in circuits driving the diaphragm known as inactivity-induced phrenic motor facilitation (iPMF), a rebound increase in phrenic inspiratory output observed once respiratory neural drive is restored. The mechanisms underlying iPMF are unknown. Here, we demonstrate in anesthetized rats that spinal mechanisms give rise to iPMF and that iPMF consists of at least two mechanistically distinct phases: (1) an early, labile phase that requires atypical PKC (PKCζ and/or PKCι/λ) activity to transition to a (2) late, stable phase. Early (but not late) iPMF is associated with increased interactions between PKCζ/ι and the scaffolding protein ZIP (PKCζ-interacting protein)/p62 in spinal regions associated with the phrenic motor pool. Although PKCζ/ι activity is necessary for iPMF, spinal atypical PKC activity is not necessary for phrenic long-term facilitation (pLTF) following acute intermittent hypoxia, an activity-independent form of spinal respiratory plasticity. Thus, while iPMF and pLTF both manifest as prolonged increases in phrenic burst amplitude, they arise from distinct spinal cellular pathways. Our data are consistent with the hypotheses that (1) local mechanisms sense and respond to reduced respiratory-related activity in the phrenic motor pool and (2) inactivity-induced increases in phrenic inspiratory output require local PKCζ/ι activity to stabilize into a long-lasting iPMF. Although the physiological role of iPMF is unknown, we suspect that iPMF represents a compensatory mechanism, assuring adequate motor output in a physiological system in which prolonged inactivity ends life.

Spinal TNFα is necessary for inactivity-induced phrenic motor facilitation

•  A central neural apnoea in the absence of hypoxia elicits a form of respiratory plasticity known as inactivity‐induced phrenic motor facilitation (iPMF), a rebound increase in phrenic burst amplitude when central respiratory neural activity is restored. •  iPMF requires spinal atypical protein kinase C (aPKC) activity in spinal segments encompassing the phrenic motor nucleus. •  Here, we report novel findings that tumour necrosis factor‐α (TNFα) signalling in or near the phrenic motor pool is necessary and sufficient for iPMF as: (1) spinal TNFα inhibition inhibits iPMF; and (2) spinal TNFα elicits long‐lasting increases in phrenic burst amplitude via an aPKC‐dependent mechanism. •  These data are consistent with the hypothesis that local mechanisms operating within or near the phrenic motor pool sense and respond to reduced respiratory neural activity, and suggest that TNFα‐induced activation of aPKC near phrenic motor neurons forms part of the core cellular pathway giving rise to iPMF.