Publications by authors named "Michael T Y Lam"

8 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241438PMC
May 2021

Lungs can tell time-a highlight from 2016 ATS session on clock genes, inflammation, immunology, and sleep.

J Thorac Dis 2016 Jul;8(Suppl 7):S579-81

Division of Pulmonary, Critical Care & Sleep Medicine, La Jolla, CA 92037, USA.

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http://dx.doi.org/10.21037/jtd.2016.07.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990684PMC
July 2016

Enhancer RNAs.

Cell Cycle 2014 ;13(20):3151-2

a Department of Medicine ; University of California San Diego; La Jolla , CA USA.

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http://dx.doi.org/10.4161/15384101.2014.962860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613994PMC
September 2015

Enhancer RNAs and regulated transcriptional programs.

Trends Biochem Sci 2014 Apr 24;39(4):170-82. Epub 2014 Mar 24.

Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA; Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA. Electronic address:

A large portion of the human genome is transcribed into RNAs without known protein-coding functions, far outnumbering coding transcription units. Extensive studies of long noncoding RNAs (lncRNAs) have clearly demonstrated that they can play critical roles in regulating gene expression, development, and diseases, acting both as transcriptional activators and repressors. More recently, enhancers have been found to be broadly transcribed, resulting in the production of enhancer-derived RNAs, or eRNAs. Here, we review emerging evidence suggesting that at least some eRNAs contribute to enhancer function. We discuss these findings with respect to potential mechanisms of action of eRNAs and other ncRNAs in regulated gene expression.
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http://dx.doi.org/10.1016/j.tibs.2014.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266492PMC
April 2014

Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription.

Nature 2013 Jun 2;498(7455):511-5. Epub 2013 Jun 2.

Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.

Rev-Erb-α and Rev-Erb-β are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)-HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell-specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5' ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.
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http://dx.doi.org/10.1038/nature12209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839578PMC
June 2013

Non-coding RNAs as regulators of gene expression and epigenetics.

Cardiovasc Res 2011 Jun 9;90(3):430-40. Epub 2011 May 9.

Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.

Genome-wide studies have revealed that mammalian genomes are pervasively transcribed. This has led to the identification and isolation of novel classes of non-coding RNAs (ncRNAs) that influence gene expression by a variety of mechanisms. Here we review the characteristics and functions of regulatory ncRNAs in chromatin remodelling and at multiple levels of transcriptional and post-transcriptional regulation. We also describe the potential roles of ncRNAs in vascular biology and in mediating epigenetic modifications that might play roles in cardiovascular disease susceptibility. The emerging recognition of the diverse functions of ncRNAs in regulation of gene expression suggests that they may represent new targets for therapeutic intervention.
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http://dx.doi.org/10.1093/cvr/cvr097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096308PMC
June 2011

Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis.

Development 2008 Nov;135(22):3755-64

Department of Surgery, University of California, San Francisco, CA 94143, USA.

A mutual coordination of size between developing arteries and veins is essential for establishing proper connections between these vessels and, ultimately, a functional vasculature; however, the cellular and molecular regulation of this parity is not understood. Here, we demonstrate that the size of the developing dorsal aorta and cardinal vein is reciprocally balanced. Mouse embryos carrying gain-of-function Notch alleles show enlarged aortae and underdeveloped cardinal veins, whereas those with loss-of-function mutations show small aortae and large cardinal veins. Notch does not affect the overall number of endothelial cells but balances the proportion of arterial to venous endothelial cells, thereby modulating the relative sizes of both vessel types. Loss of ephrin B2 or its receptor EphB4 also leads to enlarged aortae and underdeveloped cardinal veins; however, endothelial cells with venous identity are mislocalized in the aorta, suggesting that ephrin B2/EphB4 signaling functions distinctly from Notch by sorting arterial and venous endothelial cells into their respective vessels. Our findings provide mechanistic insight into the processes underlying artery and vein size equilibration during angiogenesis.
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http://dx.doi.org/10.1242/dev.022475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596923PMC
November 2008

Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice.

Proc Natl Acad Sci U S A 2008 Aug 30;105(31):10901-6. Epub 2008 Jul 30.

Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, University of California, San Francisco, CA 94143, USA.

Brain arteriovenous malformations (BAVMs) can cause devastating stroke in young people and contribute to half of all hemorrhagic stroke in children. Unfortunately, the pathogenesis of BAVMs is unknown. In this article we show that activation of Notch signaling in the endothelium during brain development causes BAVM in mice. We turned on constitutively active Notch4 (int3) expression in endothelial cells from birth by using the tetracycline-regulatable system. All mutants developed hallmarks of BAVMs, including cerebral arteriovenous shunting and vessel enlargement, by 3 weeks of age and died by 5 weeks of age. Twenty-five percent of the mutants showed signs of neurological dysfunction, including ataxia and seizure. Affected mice exhibited hemorrhage and neuronal cell death within the cerebral cortex and cerebellum. Strikingly, int3 repression resolved ataxia and reversed the disease progression, demonstrating that int3 is not only sufficient to induce, but also required to sustain the disease. We show that int3 expression results in widespread enlargement of the microvasculature, which coincided with a reduction in capillary density, linking vessel enlargement to Notch's known function of inhibiting vessel sprouting. Our data suggest that the Notch pathway is a molecular regulator of BAVM pathogenesis in mice, and offer hope that their regression might be possible by targeting the causal molecular lesion.
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http://dx.doi.org/10.1073/pnas.0802743105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504798PMC
August 2008
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