Changes in energy metabolism and respiration in different tracheal narrowing in rats

Why obstructive sleep apnea (OSA) treatment does not completely restore healthy metabolic physiology is unclear. In rats, the need for respiratory homeostasis maintenance following airway obstruction (AO) is associated with a loss of thermoregulation and abnormal metabolic physiology that persists following successful obstruction removal. Here, we explored the effect of two different types of tracheal narrowing, i.e., AO and mild airway obstruction (mAO), and its removal on respiratory homeostasis and metabolic physiology. We show that after ten weeks, mAO vs. AO consumes sufficient energy that is required to maintain respiratory homeostasis and thermoregulation. Obstruction removal was associated with largely irreversible increased feeding associated with elevated serum ghrelin, hypothalamic growth hormone secretagogue receptor 1a, and a phosphorylated Akt/Akt ratio, despite normalization of breathing and energy requirements. Our study supports the need for lifestyle eating behavior management, in addition to endocrine support, in order to attain healthy metabolic physiology in OSA patients.

SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress

The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR)7/9- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-γ-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient biotransformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage’s respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells’ ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress.

Type II alveolar cell MHCII improves respiratory viral disease outcomes while exhibiting limited antigen presentation

Type II alveolar cells (AT2s) are critical for basic respiratory homeostasis and tissue repair after lung injury. Prior studies indicate that AT2s also express major histocompatibility complex class II (MHCII) molecules, but how MHCII expression by AT2s is regulated and how it contributes to host defense remain unclear. Here we show that AT2s express high levels of MHCII independent of conventional inflammatory stimuli, and that selective loss of MHCII from AT2s in mice results in modest worsening of respiratory virus disease following influenza and Sendai virus infections. We also find that AT2s exhibit MHCII presentation capacity that is substantially limited compared to professional antigen presenting cells. The combination of constitutive MHCII expression and restrained antigen presentation may position AT2s to contribute to lung adaptive immune responses in a measured fashion, without over-amplifying damaging inflammation.

Type II alveolar cells with constitutive expression of MHCII and limited antigen presentation capacity contribute to improved respiratory viral disease outcomes

Type II alveolar cells (AT2s) are critical for basic respiratory homeostasis and tissue repair after lung injury. Prior studies indicate that AT2s also express major histocompatibility complex II (MHCII) molecules, but how MHCII expression by AT2s is regulated and how it contributes to host defense remain unclear. Here we show that AT2s express high levels of MHCII independent of conventional inflammatory stimuli, and that selective loss of MHCII from AT2s in mice results in the worsening of respiratory virus disease following influenza and Sendai virus infections. We also find that AT2s exhibit MHCII presentation capacity that is substantially limited in comparison to professional antigen presenting cells. The combination of constitutive MHCII expression and restrained presentation may position AT2s to contribute to lung adaptive immune responses in a measured fashion, without over-amplifying damaging inflammation.

The retrotrapezoid nucleus and the neuromodulation of breathing

Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators in order to maintain respiratory homeostasis. Modulators such as acetylcholine, norepinephrine, histamine, serotonin (5-HT), adenosine triphosphate (ATP), substance P, somatostatin, bombesin, orexin, and leptin can serve complementary or off-setting functions depending on the target cell type and signalling mechanisms engaged. Abnormalities in any of these modulatory mechanisms can destabilize breathing, suggesting modulatory mechanisms are not overly redundant but rather work in concert to maintain stable respiratory output. The present review focuses on the modulation of a specific cluster of neurons located in the ventral medullary surface, named retrotrapezoid nucleus, that is activated by changes in tissue CO2/H+ and regulates several aspects of breathing, including inspiration and active expiration.

Irreversible metabolic abnormalities following chronic upper airway loading

Study Objectives Treatment of obstructive sleep apnea increases obesity risk by an unclear mechanism. Here, we explored the effects of upper airway obstruction and its removal on respiratory homeostasis, energy expenditure, and feeding hormones during the sleep/wake cycle from weaning to adulthood. Methods The tracheas of 22-day-old rats were narrowed, and obstruction removal was performed on post-surgery day 14. Energy expenditure, ventilation, and hormone-regulated feeding were analyzed during 49 days before and after obstruction. Results Energy expenditure increased and body temperature decreased in upper airway obstruction and was only partially recovered in obstruction removal despite normalization of airway resistance. Increased energy expenditure was associated with upregulation of ventilation. Decreased body temperature was associated with decreased brown adipose tissue uncoupling protein 1 level, suppressed energy expenditure response to norepinephrine, and decreased leptin level. Upper airway obstructed animals added less body weight, in spite of an increase in food intake, due to elevated hypothalamic orexin and neuropeptide Y and plasma ghrelin. Animals who underwent obstruction removal fed more due to an increase in hypothalamic neuropeptide Y and plasma ghrelin. Conclusions The need to maintain respiratory homeostasis is associated with persistent abnormal energy metabolism and hormonal regulation of feeding. Surgical treatment per se may not be sufficient to correct energy homeostasis, and endocrine regulation of feeding may have a larger effect on weight change.

Study of cardiovascular and respiratory synchronization in different types of breathing

Актуальность. В работе обоснован диагностический алгоритм, позволяющий объективно устанавливать критерии синхронизации в регуляции кардио-респираторной системы, обеспечивающей адекватный уровень адаптации организма при умеренных внешних воздействиях. Целью данной работы явилось изучение возможных параметров сопряжённости сердечного, сосудистого и дыхательного ритмов при выполнении функциональных проб: пробы с фиксированной частотой дыхания и ступенчато-возрастающей умеренной физической нагрузкой. Методы. Для реализации диагностического алгоритма был использован действующий макет комплекса «Спироартериокардиоритмограф-01», адаптированный под совместное использование с велоэргометром. Подобный подход обеспечивает объективный мониторинг сердечно-дыхательного синхронизма в динамике разнообразных внешних воздействий на организм. Результаты. На основе прямых динамических показателей обоснован алгоритм расчета отношения минутного объема кровообращения и минутного объема дыхания, отражающий степень функционального баланса сердечно-дыхательного гомеостаза. Выводы. Многопараметровость, быстрота и неинвазивность исследований обеспечат востребованность данной методологии в разнообразных направлениях предиктивной диагностики. The authors justified a diagnostic algorithm for establishing objective criteria of cardiovascular and respiratory synchronization, which provides an adequate adaptive response to different external factors. For evaluation of the diagnostic algorithm, the Spiroarteriokardioritmograf-01 complex compatible with a bicycle ergometer was used. This approach provides objective monitoring of cardiovascular and respiratory synchronism under the influence of various external factors. Multiparameter, fast, and non-invasive features of these studies will cover a demand for this method in predictive diagnostics. Based on direct dynamic indicators an algorithm was substantiated for calculation of the blood flow minute volume to respiratory minute volume ratio, which reflects the degree of functional balance in the cardiovascular and respiratory homeostasis.

Respiratory protease/antiprotease balance determines susceptibility to viral infection and can be modified by nutritional antioxidants

The respiratory epithelium functions as a central orchestrator to initiate and organize responses to inhaled stimuli. Proteases and antiproteases are secreted from the respiratory epithelium and are involved in respiratory homeostasis. Modifications to the protease/antiprotease balance can lead to the development of lung diseases such as emphysema or chronic obstructive pulmonary disease. Furthermore, altered protease/antiprotease balance, in favor for increased protease activity, is associated with increased susceptibility to respiratory viral infections such as influenza virus. However, nutritional antioxidants induce antiprotease expression/secretion and decrease protease expression/activity, to protect against viral infection. As such, this review will elucidate the impact of this balance in the context of respiratory viral infection and lung disease, to further highlight the role epithelial cell-derived proteases and antiproteases contribute to respiratory immune function. Furthermore, this review will offer the use of nutritional antioxidants as possible therapeutics to boost respiratory mucosal responses and/or protect against infection.