Obstructive sleep apnea (OSA) has been linked to increased mortality in pulmonary fibrosis. Its key feature, chronic intermittent hypoxia (CIH), can lead to oxidative stress and inflammation, known to lead to fibrotic pathology in other organs. We tested the effects of CIH in an animal model of bleomycin-induced lung fibrosis. Sprague Dawley rats were instilled intratracheally with bleomycin (Blm) or saline (Sal), and exposed to CIH or normal air (Norm) for 9 or 30 days. Pulmonary function was tested and lungs were harvested for histological and molecular analyses. In Blm-treated animals, 30days of CIH compared to Norm increased total lung collagen content (p=0.008) and reduced Quasi-static lung compliance (p=0.04). CIH upregulated lipid peroxidation and increased NF-κB activation, IL-17 mRNA and Col1α1 mRNA expression. Our results indicate that following Blm-induced lung injury, CIH amplifies collagen deposition via oxidative and inflammatory pathways, culminating in stiffer lungs. Thus, OSA may augment fibrosis in patients with interstitial lung disease.
Rats exposed to postnatal hyperoxia develop right ventricular (RV) dysfunction, mild pulmonary hypertension, and dysregulated cardiac mitochondrial biogenesis when aged to one year, with the degree of cardiac dysfunction and pulmonary hypertension similar to that previously described in young adults born preterm. Here, we sought to understand the impact of postnatal hyperoxia exposure on RV hemodynamic and mitochondrial function across the life span. In Methods, pups from timed-pregnant Sprague-Dawley rats were randomized to normoxia or hyperoxia [fraction of inspired oxygen ([Formula: see text]), 0.85] exposure for the first 14 days of life, a commonly used model of chronic lung disease of prematurity. RV hemodynamic and mitochondrial function were assessed by invasive measurement of RV pressure-volume loops and by high-resolution respirometry at postnatal day 21 (P21), P90, and P365. In Results, at P21, hyperoxia-exposed rats demonstrated severe pulmonary hypertension and RV dysfunction, accompanied by depressed mitochondrial oxidative capacity. However, significant upregulation of mitochondrial biogenesis at P21 as well as improved afterload led to complete RV hemodynamic and mitochondrial recovery at P90. Mitochondrial DNA mutations were significantly higher by P90 and associated with significant late RV mitochondrial and hemodynamic dysfunction at P365. In conclusion, there appears to be a “honeymoon period” where cardiac hemodynamic and mitochondrial function normalizes following postnatal hyperoxia exposure, only to decline again with ongoing aging. This finding may have significant implications if a long-term pulmonary vascular screening program were to be developed for children or adults with a history of severe prematurity. Further investigation into the mechanisms of recovery are warranted. NEW & NOTEWORTHY Premature birth is associated with increased risk for cardiac dysfunction and failure throughout life. Here, we identify bimodal right ventricular dysfunction after postnatal hyperoxia exposure. Mitochondrial biogenesis serves as an early adaptive feature promoting recovery of cardiac hemodynamic and mitochondrial function. However, the accumulation of mitochondrial DNA mutations results in late mitochondrial and right ventricular dysfunction. This bimodal right ventricular dysfunction may have important implications for the development of screening programs in the preterm population.
Introduction Modern medicine has made enormous progress in the past 150 years including the development of vaccines and pharmaceutical therapies. However, to date there is little progress in developing therapies that speed the healing of injured tissues. Hyperbaric oxygen therapy (HBOT) is a FDA approved therapy for non‐healing wounds consisting of daily intermittent doses of elevated partial pressure of oxygen (PO2) above 1520 torr. The hypothetical mechanism is its influence on mobilizing stem cells via cell signaling and gene transcription at effector tissues. Preclinical research showed a regimen of HBOT resulted in mobilization of stem cells and increased vasculogenesis in a wound healing model. Our study sought to determine if partial pressures of oxygen less than 760 torr would also mobilize stem cells. Methods Twelve, 10‐week‐old Sprague Dawley rats were randomly divided into two groups. The treatment group was exposed to a hyperoxic environment with a PO2 = 319 torr. The control group was exposed to room air (PO2 = 159 torr). Treatments were performed 5 days per week for 2 hours daily for a total of 10 treatment days (20 hours). Animals were sacrificed and approximately 8 ml of venous blood was harvested from the inferior vena cava. Red blood cells were lysed and plasma was drawn off and frozen. Remaining cells were prepared for flow cytometry by exposing them to cell surface marker antibodies for CD34+and CD 133+. These cells were then analyzed on a BD LSRII flow cytometer using DIVA software. Analysis was completed using FlowJo software. Statistics were performed using an unpaired t‐test with a p<.05 to indicate significance. Results Animals treated with a PO2 = 319 torr showed an increase (p = 0.045) in mobilized CD133+/34 endothelial progenitor cells (EPC's), while no differences were seen in CD133−/34+ hematopoietic stem progenitor cells (HSPC's) when compared to the control group. Discussion We hypothesized that there would be an increase in the CD133+/34− EPC's and an increase in CD133−/34+ HSPC's. Although our hypothesis was correct regarding the EPC's we did not see an increase in HSPC's as expected. CD133+/34− EPC's are considered more primitive stem cells than the CD133−/34+ HSPC's. CD133+/34− EPC's are capable of differentiation into CD133−/34+ HSPC's as they progress along the oligopotent path to maturation. Future research should include a pathological condition to test for changes in stem cell populations and the effects of pathology on stem cell differentiation. Our data suggest that low doses of daily intermittent hyperoxia mobilize the population of CD133+/34− EPC's. These EPC's have been shown in vivo to increase vascular density in a skin graft model. Further study is needed to determine what amount of intermittent hyperoxia treatment results in the most efficacious treatment in an injury model (increased stem cell mobilization, vasculogenesis and functional recovery). Support or Funding Information DOD Navy ‐ N00024‐17‐C‐4318 This abstract is from the Experimental Biology 2018 Meetin...
Chronic hypoxia (CH)-induced pulmonary hypertension (PH) results, in part, from TH17 cell-mediated perivascular inflammation. However, the antigen/s involved are unknown. Cellular immunity to collagen type V (col V) develops after ischemia-reperfusion injury during lung transplant and is mediated by naturally occurring "nTH17" cells. COL5A1 codifies for the α1 helix of col V, which is normally hidden from the immune system within type I collagen in the extracellular matrix. COL5A1 promoter analysis revealed NFATc3 binding sites. Therefore, we hypothesized that smooth muscle NFATc3 upregulates col V expression leading to nTH17 cell-mediated autoimmunity to col V in response to CH, representing an upstream mechanism in PH development. To test our hypothesis, we measured indexes of PH in inducible, smooth muscle cell (SMC) specific NFATc3 KO mice exposed to either CH (380 mmHg) or normoxia and compared them to wild type (WT) mice. KO mice did not develop PH. In addition, COL5A1 was one of the 1792 genes differentially affected by both CH and SMC NFATc3 in isolated intrapulmonary arteries, which was confirmed by RT-PCR and immunostaining. Cellular immunity to col V was determined using a transvivo delayed-type hypersensitivity assay (Tv-DTH). Tv-DTH response was only evident when using splenocytes from control mice exposed to CH but not from KO mice, and mediated by nTH17 cells. Our results suggest that SMC NFATc3 is important for CH-induced PH in adult mice, in part, by regulating the expression of the lung self-antigen COL5A1 contributing to col V-reactive nTH17-mediated inflammation and hypertension.
IntroductionHyperbaric air (HBA) was first used pharmaceutically in 1662 to treat lung disease. Extensive use in Europe and North America followed throughout the 19th century to treat pulmonary and neurological disorders. HBA reached its zenith in the early 20th century when cyanotic, moribund “Spanish flu pandemic” patients turned normal color and regained consciousness within minutes after HBA treatment. Since that time the 78% Nitrogen fraction in HBA has been completely displaced by 100% oxygen to create the modern pharmaceutical hyperbaric oxygen therapy (HBOT), a powerful treatment that is FDA approved for multiple indications. Current belief purports oxygen as the active element mobilizing stem progenitor cells (SPCs) in HBOT, but hyperbaric air, which increases tensions of both oxygen and nitrogen, has been untested until now. In this study we test HBA for SPC mobilization, cytokine and chemokine expression, and complete blood count.MethodsTen 34–35-year-old healthy volunteers were exposed to 1.27ATA (4 psig/965 mmHg) room air for 90 min, M-F, for 10 exposures over 2-weeks. Venous blood samples were taken: (1) prior to the first exposure (served as the control for each subject), (2) directly after the first exposure (to measure the acute effect), (3) immediately prior to the ninth exposure (to measure the chronic effect), and (4) 3 days after the completion of tenth/final exposure (to assess durability). SPCs were gated by blinded scientists using Flow Cytometry.ResultsSPCs (CD45dim/CD34+/CD133-) were mobilized by nearly two-fold following 9 exposures (p = 0.02) increasing to three-fold 72-h post completion of the final (10th) exposure (p = 0.008) confirming durability.DiscussionThis research demonstrates that SPCs are mobilized, and cytokines are modulated by hyperbaric air. HBA likely is a therapeutic treatment. Previously published research using HBA placebos should be re-evaluated to reflect a dose treatment finding rather than finding a placebo effect. Our findings of SPC mobilization by HBA support further investigation into hyperbaric air as a pharmaceutical/therapy.
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