Browsing by Author "Flannigan, Kyle L."

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    Anti-Inflammatory and Cytoprotective Actions of Hydrogen Sulfide: Translation to Therapeutics
    (Antioxidants & Redox Signaling, 2015-04-15) Wallace, John L.; Blackler, Rory W.; Chan, Melissa V.; Da Silva, Gabriela J.; Elsheikh, Wagdi; Flannigan, Kyle L.; Gamaniek, Iulia; Manko, Anna; Wang, Lu; Motta, Jean-Paul; Buret, Andre G.
    Significance: There is a rapidly expanding body of evidence for important roles of hydrogen sulfide in protecting against tissue injury, reducing inflammation, and promoting repair. There is also growing evidence that H2S can be successfully exploited in drug development. Recent Advances: H2S synthesis and degradation are regulated in circumstances of inflammation and injury so as to promote repair and re-establish homeostasis. Novel H2S-releasing drugs exhibit enhanced anti-inflammatory and pro-restorative effects, while having reduced adverse effects in many tissues. Critical Issues: H2S is a pleiotropic mediator, having effects on many elements in the inflammatory cascade and promoting the resolution of inflammation and injury. It also contributes significantly to mucosal defence in the gastrointestinal tract, and in host defence against infection. There is strong evidence that novel, H2S-based therapeutics are safe and effective in animal models, and several are progressing through human trials. Future Directions: A better understanding of the physiological and pathophysiological roles of H2S continues to be restrained by the lack of simple, reliable methods for measurement of H2S synthesis, and the paucity of highly selective inhibitors of enzymes that participate in endogenous H2S synthesis. On the other hand, H2S donors show promise as therapeutics for several important indications. Antioxid. Redox Signal. 22, 398–410.
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    Investigating pulmonary vascular B cells
    (2019-04-26) Podstawka, John; Yipp, Bryan G.; Hirota, Simon Andrew; Kelly, Margaret Mary; Flannigan, Kyle L.
    The lung is a vital organ which is required for gas exchange. The anatomy of the lung itself, immune molecules, and leukocytes provide the host with protection from harmful debris and pathogenic stimuli. A component of pulmonary host defense is neutrophils which are found within the lung capillary network. Within the pulmonary capillaries, there is a population of neutrophils which remains adherent to the vascular endothelium for extended periods of time and exhibits marginated behaviour. While pulmonary vascular neutrophils are important in the acute immune response of the lung, they tend to exhibit an aged and pro-inflammatory phenotype. While inflammation within the lung is necessary for host defence and is a part of wound healing, cellular infiltration of the lung significantly compromises oxygen delivery and carbon dioxide removal. Therefore, pulmonary inflammation must be tightly controlled and regulated. We previously determined that pulmonary vascular B cells regulate neutrophils via CD18-mediated interactions, labelling them MHCII+AnnexinV+, and that in the absence of B cells, the lung will develop pathological fibrotic interstitial lung disease. In this body of work, we determined that pulmonary intravascular B cells can marginate which allows them to specialize in regulating lung neutrophils. These B cells exhibit a mature, naïve, conventional B2 cell phenotype, and engage in marginated behaviour which can be mediated by CD49e or via CXCR5/CXCL13. Blocking CD49e decreased the amount B cell-neutrophil interactions taking place within the lung capillaries, and providing exogenous CXCL13 or neutralizing endogenous CXCL13 would respectively increase and decrease the amount of interactions. Moreover, we demonstrated an intratracheal injection of CXCL13 increased the number of neutrophils which exhibited an MHCII+AnnexinV+ phenotype; indicating increased regulation via B cell interactions. Thus, we acquired novel insight into how lung intravascular B cells are engaging in prolonged interactions with lung neutrophils; interactions which were previously defined as regulatory and important for maintaining inflammatory homeostasis.