Type 1 respiratory failure-induced hypoxemia triggers complex signaling responses and apoptosis in the rat brain
Authors: Barakat Rawan , Turcani Marian , Narayana Kilarkaje , Al-Sarraf Hameed , Redzic Zoran 
Published: May 2023

Type 1 respiratory failure (T1RF)is caused by lung injury or low partial pressure of O2 (PO2) in air. It is associated with secondary acute brain injury (sABI), but the mechanisms behind it are not clear and could include primary hypoxic injury, increased intracranial pressure due to hypoxemia or due to mechanical ventilation, or could be mediated by lung injury-triggered inflammation. This study aimed to elucidate the effects of T1RF-induced hypoxemia on the brain in the absence of lung injury. SD rats were exposed to 8%O2in N2 for up to 48h. We measured tissue PO2(PtO2) and cerebral blood flow (CBF) in the cerebral cortex (CC) and estimated lactate concentrations and apoptosis in the CC, ependymal layer (EL) and choroid plexuses (CPs) during the time course of hypoxemia using the TUNEL assay. Cerebrospinal fluid (CSF) samples were collected during normoxia, after 24h and 48h hypoxemia. The concentrations of 32 signaling molecules were estimated in these samples by multiplex assays. Expressions of 84 signaling molecules and 5 housekeeping genes in the CC were explored by RT2 ProfilerTM PCR Array. Numerical values are presented as mean (SD). Data was compared with one-way ANOVA and the Kruskal-Wallis test. The Mann-Kendall test was used to assess whether CBF was increasing or decreasing during hypoxemia. Fold changes in the expressions of the tested mRNAs were estimated using GeneGlobe software. Statistical significance was set at p<0.05. Hypoxemia exerted a significant effect on PtO2 in the CC (p<0.01), which was 49.5 (2.99) mmHg (n=10) during normoxia but declined to 6.4 (3.8) mmHg (n=5) after 1h hypoxemia (p<0.01 vs. normoxia) and then slowly increased, reaching 18.5 (2.8) mmHg (n=6) after 43h hypoxemia (p<0.01 vs. normoxia and 1h hypoxemia). This was accompanied by a significant increase in lactate concentrations in the CC and CSF (p<0.01), but not in plasma (p=0.055). Hypoxemia exerted significant effect on the number of apoptotic cells in the CC (p<0.01), EL (p<0.01) and CPs (p<0.01). In the CC the number of apoptotic cells was 5.63 (4.76) during normoxia, 20.48 (4.1) % after 24h hypoxemia (p<0.01 vs. control) and 32.37 (6.5) % after 48h hypoxemia (p<0.01 vs. control, p<0.05 vs. 24h hypoxemia). Any monotonic increase or decrease in the CBF during hypoxemia could not be detected (p>0.05). There was a significant effect of the duration of hypoxemia on the concentrations for the following cytokines in the CSF: IL-15, IL-17A, CXCL10, VEGF, Erythropoietin, FGF21, FSTL-1, GDF8/Myostatin, LIF and SPARC. When compared to normoxia, the expression of 11 mRNAs, most of them for pro-inflammatory cytokines, were 2-2.5 folds lower after 6h hypoxemia. Expression of mRNAs for angiogenic VEGF and pro-inflamatory IL7 were 2 folds and 2-5 folds higher after 24h and 48h hypoxemia, respectively. Our findings revealed a complex response by thebrain during T1RF-induced hypoxemiaand suggest an association between TIRF-induced hypoxemia, tissue hypoxia and sABI. This study was supported by the Kuwait University Research Sector Grants no YM 05/18 and MY 02/18. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.