Publications by authors named "Mark Hepokoski"

18 Publications

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Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: a case series and review of the literature.

Clin Infect Dis 2021 May 14. Epub 2021 May 14.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.

Background: Increased inflammation has been well defined in COVID-19, while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.

Methods: Blood was obtained serially from critically ill COVID-19 patients for eleven days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis and cytokine levels were assessed. Lung tissue was obtained immediately post-mortem for immunostaining. Pubmed searches for neutrophils, lung and COVID-19 yielded ten peer-reviewed research articles in English.

Results: Elevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified both at first measurement and across hospitalization (p<0.0001). COVID neutrophils had exaggerated oxidative burst (p<0.0001), NETosis (p<0.0001) and phagocytosis (p<0.0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of SARS-CoV-2 infected lungs available for examination (2 out of 5). While elevations in IL-8 and ANC correlated with disease severity, plasma IL-8 levels alone correlated with death.

Conclusions: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data shows that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.
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http://dx.doi.org/10.1093/cid/ciab437DOI Listing
May 2021

Inpatient Use of Metformin and Acarbose Is Associated with Reduced Mortality of COVID-19 Patients with Type 2 Diabetes Mellitus.

Res Sq 2021 Mar 26. Epub 2021 Mar 26.

Type 2 diabetes mellitus (T2DM) is a strong risk factor for complications of coronavirus disease 2019 (COVID-19). The effect of T2DM medications on COVID-19 outcomes remains unclear. In a retrospective analysis of a cohort of 131 patients with T2DM hospitalized for COVID-19 in Wuhan, we have previously found that metformin use prior to hospitalization is associated with reduced mortality. Here we continue to investigate the effects of inpatient use of T2DM medications, including metformin, acarbose, insulin, and sulfonylureas, on the mortality of COVID-19 patients with T2DM during hospitalization. We found that patients using metformin and acarbose, alone or both together, after admission were significantly more likely to survive than those who did not use either metformin or acarbose. Thus, our analyses suggest that inpatient use of metformin and acarbose together or alone during hospitalization should be studied in randomized trials.
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http://dx.doi.org/10.21203/rs.3.rs-287308/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010742PMC
March 2021

SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2.

Circ Res 2021 04 31;128(9):1323-1326. Epub 2021 Mar 31.

Xi'an Jiaotong University Health Science Center. Cardiology, Department of Medicine (Jiao Zhang, M. He, H.S., Y.Z., Y.C., J.Y.-J.S.), University of California, San Diego, La Jolla, CA.

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http://dx.doi.org/10.1161/CIRCRESAHA.121.318902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091897PMC
April 2021

Altered lung metabolism and mitochondrial DAMPs in lung injury due to acute kidney injury.

Am J Physiol Lung Cell Mol Physiol 2021 05 10;320(5):L821-L831. Epub 2021 Feb 10.

VA San Diego Healthcare System, San Diego, California.

Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury because of AKI.
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http://dx.doi.org/10.1152/ajplung.00578.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174821PMC
May 2021

Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19.

Endocr Pract 2020 Oct;26(10):1166-1172

From the Department of Medicine, University of California, San Diego, La Jolla, California.

Objective: Although type 2 diabetes mellitus (T2DM) has been reported as a risk factor for coronavirus disease 2019 (COVID-19), the effect of pharmacologic agents used to treat T2DM, such as metformin, on COVID-19 outcomes remains unclear. Metformin increases the expression of angiotensin converting enzyme 2, a known receptor for severe acute respiratory syndrome coronavirus 2. Data from people with T2DM hospitalized for COVID-19 were used to test the hypothesis that metformin use is associated with improved survival in this population.

Methods: Retrospective analyses were performed on de-identified clinical data from a major hospital in Wuhan, China, that included patients with T2DM hospitalized for COVID-19 during the recent epidemic. One hundred and thirty-one patients diagnosed with COVID-19 and T2DM were used in this study. The primary outcome was mortality. Demographic, clinical characteristics, laboratory data, diabetes medications, and respiratory therapy data were also included in the analysis.

Results: Of these 131 patients, 37 used metformin with or without other antidiabetes medications. Among the 37 metformin-taking patients, 35 (94.6%) survived and 2 (5.4%) did not survive. The mortality rates in the metformin-taking group versus the non-metformin group were 5.4% (2/37) versus 22.3% (21/94). Using multivariate analysis, metformin was found to be an independent predictor of survival in this cohort (P = .02).

Conclusion: This study reveals a significant association between metformin use and survival in people with T2DM diagnosed with COVID-19. These clinical data are consistent with potential benefits of the use of metformin for COVID-19 patients with T2DM.
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http://dx.doi.org/10.4158/EP-2020-0466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834011PMC
October 2020

SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2.

bioRxiv 2020 Dec 4. Epub 2020 Dec 4.

Coronavirus disease 2019 (COVID-19) includes the cardiovascular complications in addition to respiratory disease. SARS-CoV-2 infection impairs endothelial function and induces vascular inflammation, leading to endotheliitis. SARS-CoV-2 infection relies on the binding of Spike glycoprotein (S protein) to angiotensin converting enzyme 2 (ACE2) in the host cells. We show here that S protein alone can damage vascular endothelial cells (ECs) in vitro and in vivo, manifested by impaired mitochondrial function, decreased ACE2 expression and eNOS activity, and increased glycolysis. The underlying mechanism involves S protein downregulation of AMPK and upregulation of MDM2, causing ACE2 destabilization. Thus, the S protein-exerted vascular endothelial damage via ACE2 downregulation overrides the decreased virus infectivity.
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http://dx.doi.org/10.1101/2020.12.04.409144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724674PMC
December 2020

ACE2, Metformin, and COVID-19.

iScience 2020 Jul 31;23(9):101425. Epub 2020 Jul 31.

Department of Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Division of Cardiology, University of California, San Diego, La Jolla, CA 92023, USA. Electronic address:

COVID-19 is becoming a leading cause of mortality throughout the world, and few effective therapies are currently available. Angiotensin converting enzyme 2 (ACE2) is essential to COVID-19 pathogenesis, as the binding of SARS-CoV-2 spike protein (S protein) is required for viral entry and development of COVID-19. ACE2 regulates the protective arm of the renin-angiotensin-aldosterone system (RAAS) that endows anti-hypertensive and anti-inflammatory effects in the cardiovascular and pulmonary systems. Preclinical data suggest ACE2 might be downregulated after SARS-CoV-2 binding, and treatments that increase ACE2 may prevent cardiopulmonary injury. Development, testing, and mass production of novel ACE2 therapies may take years, whereas more effective treatments for COVID-19 are needed urgently. Metformin is a widely available anti-diabetic agent that has an excellent safety profile, and clinical and preclinical data suggest metformin may offer cardiopulmonary protection in COVID-19 via enhanced ACE2 expression.
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http://dx.doi.org/10.1016/j.isci.2020.101425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452173PMC
July 2020

Mitochondrial transplantation: respiration rescue in respiratory failure.

Authors:
Mark Hepokoski

Am J Physiol Lung Cell Mol Physiol 2020 01 27;318(1):L76-L77. Epub 2019 Nov 27.

VA San Diego Healthcare System, San Diego, California.

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http://dx.doi.org/10.1152/ajplung.00478.2019DOI Listing
January 2020

Can We DAMPen the Cross-Talk between the Lung and Kidney in the ICU?

Am J Respir Crit Care Med 2018 Nov;198(9):1220-1222

Division of Pulmonary and Critical Care Medicine, University of California San Diego, San Diego, California.

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http://dx.doi.org/10.1164/rccm.201712-2573RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221576PMC
November 2018

Ventilator-Induced Kidney Injury: Are Novel Biomarkers the Key to Prevention?

Nephron 2018 11;140(2):90-93. Epub 2018 Jul 11.

Division of Pulmonary and Critical Care Medicine, University of California San Diego, La Jolla, California, USA.

Mechanical ventilation is associated with significant increases in the risk of acute kidney injury (AKI). The rate of AKI due to mechanical ventilation and the associated mortality remain unacceptably high. Preventative and therapeutic strategies are clearly lacking. Ventilator-induced kidney injury is believed to occur due to changes in hemodynamics that impair renal perfusion, neurohumoral-mediated alterations in intra-renal blood flow, and systemic inflammatory mediators generated by ventilator-induced lung injury. The risk of injury to the kidney by these mechanisms may be modified by open lung protective ventilation with low tidal volumes and high positive end expiratory pressure. However, these strategies may also increase the risk of injury in some settings, and clinicians have limited means to identify the optimal ventilator strategy for each specific patient. Novel urinary biomarkers have demonstrated the ability to predict AKI prior to classic clinical signs such as decreased urine output and increased creatinine. These biomarkers may serve as an early indication to intensivists of an injurious ventilator strategy and failure of traditional management.
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http://dx.doi.org/10.1159/000491557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165693PMC
September 2019

Prone positioning in acute respiratory distress syndrome: why aren't we using it more?

J Thorac Dis 2018 Apr;10(Suppl 9):S1020-S1024

Division of Pulmonary and Critical Care Medicine, University of California San Diego, San Diego, CA, USA.

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http://dx.doi.org/10.21037/jtd.2018.04.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949405PMC
April 2018

Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice.

Am J Physiol Regul Integr Comp Physiol 2018 06 31;314(6):R834-R847. Epub 2018 Jan 31.

Division of Physiology, Department of Medicine, University of California , San Diego, California.

Electronic (e)-cigarettes theoretically may be safer than conventional tobacco. However, our prior studies demonstrated direct adverse effects of e-cigarette vapor (EV) on airway cells, including decreased viability and function. We hypothesize that repetitive, chronic inhalation of EV will diminish airway barrier function, leading to inflammatory protein release into circulation, creating a systemic inflammatory state, ultimately leading to distant organ injury and dysfunction. C57BL/6 and CD-1 mice underwent nose only EV exposure daily for 3-6 mo, followed by cardiorenal physiological testing. Primary human bronchial epithelial cells were grown at an air-liquid interface and exposed to EV for 15 min daily for 3-5 days before functional testing. Daily inhalation of EV increased circulating proinflammatory and profibrotic proteins in both C57BL/6 and CD-1 mice: the greatest increases observed were in angiopoietin-1 (31-fold) and EGF (25-fold). Proinflammatory responses were recapitulated by daily EV exposures in vitro of human airway epithelium, with EV epithelium secreting higher IL-8 in response to infection (227 vs. 37 pg/ml, respectively; P < 0.05). Chronic EV inhalation in vivo reduced renal filtration by 20% ( P = 0.017). Fibrosis, assessed by Masson's trichrome and Picrosirius red staining, was increased in EV kidneys (1.86-fold, C57BL/6; 3.2-fold, CD-1; P < 0.05), heart (2.75-fold, C57BL/6 mice; P < 0.05), and liver (1.77-fold in CD-1; P < 0.0001). Gene expression changes demonstrated profibrotic pathway activation. EV inhalation altered cardiovascular function, with decreased heart rate ( P < 0.01), and elevated blood pressure ( P = 0.016). These data demonstrate that chronic inhalation of EV may lead to increased inflammation, organ damage, and cardiorenal and hepatic disease.
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http://dx.doi.org/10.1152/ajpregu.00270.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032308PMC
June 2018

Renal Oxygenation and Hemodynamics in Kidney Injury.

Nephron 2017 15;137(4):260-263. Epub 2017 Jun 15.

Division of Nephrology-Hypertension, University of California, San Diego School of Medicine and VA San Diego Healthcare System, San Diego, CA, USA.

Acute kidney injury (AKI) continues to be a major therapeutic challenge. Despite significant advances made in cellular and molecular pathophysiology of AKI, major gaps in knowledge exist regarding the changes in renal hemodynamics and oxygenation in the early stages and through the continuum of AKI. Particular features of renal hemodynamics and oxygenation increase the susceptibility of the kidney to sustain injury due to oxygen demand-supply mismatch and also play an important role in the recovery and repair from AKI as well as the transition of AKI to chronic kidney disease. However, lack of well-established physiological biomarkers and noninvasive imaging techniques limit our understanding of the interactions between renal macro and microcirculation and tissue oxygenation in AKI. Advances in our ability to assess these parameters in preclinical and clinical AKI will enable the development of targeted therapeutics to improve clinical outcomes.
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http://dx.doi.org/10.1159/000477830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732093PMC
February 2019

Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney.

Am J Physiol Renal Physiol 2017 04 9;312(4):F654-F660. Epub 2016 Nov 9.

Veterans Affairs San Diego Healthcare System, San Diego, California;

In critical illness, such as sepsis or the acute respiratory distress syndrome, acute kidney injury (AKI) is common and associated with increased morbidity and mortality. Mechanical ventilation in critical illnesses is also a risk factor for AKI, but it is potentially modifiable. Injurious ventilation strategies may lead to the systemic release of inflammatory mediators from the lung due to ventilator induced lung injury (VILI). The systemic consequences of VILI are difficult to differentiate clinically from other systemic inflammatory syndromes, such as sepsis. The purpose of this study was to identify unique changes in the expression of inflammatory mediators in kidney tissue in response to VILI compared with systemic sepsis to gain insight into direct effects of VILI on the kidney. Four groups of mice were compared-mice with sepsis from cecal ligation and puncture (CLP), mice subjected to injurious mechanical ventilation with high tidal volumes (VILI), mice exposed to CLP followed by VILI (CLP+VILI), and sham controls. Protein expression of common inflammatory mediators in kidneys was analyzed using a proteome array and confirmed by Western blot analysis or ELISA. VEGF and VCAM-1 were found to be significantly elevated in kidneys from VILI mice compared with sham and CLP. Angiopoietin-2 was significantly increased in CLP+VILI compared with CLP alone and was also correlated with higher levels of AKI biomarker, neutrophil gelatinase-associated lipocalin. These results suggest that VILI alters the renal expression of VEGF, VCAM-1, and angiopoietin-2, and these proteins warrant further investigation as potential biomarkers and therapeutic targets.
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http://dx.doi.org/10.1152/ajprenal.00523.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407070PMC
April 2017

Update in Critical Care Medicine: Evidence Published in 2016.

Ann Intern Med 2017 04 30;166(7):W20-W26. Epub 2017 Mar 30.

From the University of California, San Diego, La Jolla, California.

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http://dx.doi.org/10.7326/M17-0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483325PMC
April 2017

Spontaneous Pneumothorax Complicating Chronic Hepatic Hydrothorax: Successful Treatment by Small Bore Chest Tube.

J Bronchology Interv Pulmonol 2016 Oct;23(4):e43-e45

*Department of Medicine, VA San Diego Healthcare System †Department of Medicine, University of California at San Diego San Diego, CA ‡Department of Medicine, Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1097/LBR.0000000000000324DOI Listing
October 2016

Mechanical ventilation in acute respiratory distress syndrome at ATS 2016: the search for a patient-specific strategy.

J Thorac Dis 2016 Jul;8(Suppl 7):S550-2

UCSD Division of Pulmonary, Critical Care & Sleep Medicine, 9300 Campus Point Drive #7381, La Jolla, CA 92037, USA.

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http://dx.doi.org/10.21037/jtd.2016.07.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990680PMC
July 2016

Mechanisms and implications of the link between sleep apnoea and chronic kidney disease.

Respirology 2016 May 30;21(4):578-9. Epub 2016 Mar 30.

Division of Pulmonary, Critical Care & Sleep Medicine, University of California San Diego, San Diego, CA, USA.

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http://dx.doi.org/10.1111/resp.12796DOI Listing
May 2016