Anti‐inflammatory effects of β2 adrenergic receptor agonists in experimental acute lung injury

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154493/1/fsb2026005038.pd

Complementâ induced activation of the cardiac NLRP3 inflammasome in sepsis

Cardiac dysfunction develops during sepsis in humans and rodents. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we investigated the role of the NLRP3 inflammasome in the heart. Mouse heart homogenates from shamâ procedure mice contained high mRNA levels of NLRP3 and ILâ 1β. Usingthe inflamm a some protocol, exposure of cardiomyocytes (CMs) to LPS followed by ATP or nigericin caused release of mature ILâ 1β. Immuno staining of left ventricular frozen sections before and 8 h after CLP revealed the presence of NLRP3 and ILâ 1β proteins inCMs. CLP caused substantial increases in mRNAs for ILâ 1β and NLRP3 in CMs which are reduced in the absence of either C5aR1 or C5aR2. After CLP, NLRP32/2 mice showed reduced plasma levels of ILâ 1βand ILâ 6. In vitro exposure of wildâ type CMs to recombinant C5a (rC5a) cause delevations in both cytosolic and nuclear/mitochondrial reactive oxygen species (ROS), which were C5aâ receptor dependent. Use of a selective NOX2 inhibitor prevented increased cytosolic and nuclear/mitochondrial ROS levels and release of ILâ 1β. Finally, NLRP32/2 mice had reduced defects in echo/Doppler parameters in heart afterCLP. These studies establish that the NLRP3 inflammasome contributes to the cardiomyopathy of polymicrobial sepsis.â Kalbitz, M., Fattahi, F., Grailer, J. J., Jajou, L., Malan, E. A., Zetoune, F. S., Huberâ Lang, M., Russell, M. W., Ward, P. A. Complementâ induced activation of the cardiac NLRP3 inflammasome in sepsis. FASEB J. 30, 3997â 4006 (2016). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154362/1/fsb2fasebj30120728r.pd

Tyrosine kinase 2 promotes sepsis‐associated lethality by facilitating production of interleukin‐27

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141056/1/jlb0123-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141056/2/jlb0123.pd

Extracellular histones are essential effectors of C5aR‐ and C5L2‐mediated tissue damage and inflammation in acute lung injury

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154331/1/fsb2027012034.pd

Role of extracellular histones in the cardiomyopathy of sepsis

The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca2+]i levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nachtâ , LRRâ , and PYDâ domainsâ containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca2+]i, as wellas defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction.â Kalbitz, M., Grailer, J. J., Fattahi, F., Jajou, L., Herron, T. J., Campbell, K. F., Zetoune, F. S., Bosmann, M., Sarma, J. V., Huberâ Lang, M., Gebhard, F., Loaiza, R., Valdivia, H. H., Jalife, J., Russell, M. W., Ward, P. A. Role of extracellular histones in the cardiomyopathy of sepsis. FASEB J. 29, 2185â 2193 (2015). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154273/1/fsb2fj14268730.pd

Septicaemia models using Streptococcus pneumoniae and Listeria monocytogenes: understanding the role of complement properdin

Streptococcus pneumoniae and Listeria monocytogenes, pathogens which can cause severe infectious disease in human, were used to infect properdin-deficient and wildtype mice. The aim was to deduce a role for properdin, positive regulator of the alternative pathway of complement activation, by comparing and contrasting the immune response of the two genotypes in vivo. We show that properdin-deficient and wildtype mice mounted antipneumococcal serotype-specific IgM antibodies, which were protective. Properdin-deficient mice, however, had increased survival in the model of streptococcal pneumonia and sepsis. Low activity of the classical pathway of complement and modulation of FcγR2b expression appear to be pathogenically involved. In listeriosis, however, properdin-deficient mice had reduced survival and a dendritic cell population that was impaired in maturation and activity. In vitro analyses of splenocytes and bone marrow-derived myeloid cells support the view that the opposing outcomes of properdin-deficient and wildtype mice in these two infection models is likely to be due to a skewing of macrophage activity to an M2 phenotype in the properdin-deficient mice. The phenotypes observed thus appear to reflect the extent to which M2- or M1-polarised macrophages are involved in the immune responses to S. pneumoniae and L. monocytogenes. We conclude that properdin controls the strength of immune responses by affecting humoral as well as cellular phenotypes during acute bacterial infection and ensuing inflammation

Vascular endothelial growth factor receptor inhibitor SU5416 suppresses lymphocyte generation and immune responses in mice by increasing plasma corticosterone.

Inhibitors of vascular endothelial growth factor and its receptors (VEGFRs) are attractive therapeutic candidates for cancer treatment. One such small molecule VEGFR inhibitor, SU5416, limits angiogenesis in vivo and is widely used for investigating VEGFR signaling in tumor pathophysiology. Herein, we describe novel actions of SU5416 on the immune system. Treatment of mice with SU5416 for 3 days induced significant reductions in size and cellularity of peripheral lymph nodes. Interestingly, SU5416 did not affect initial lymphocyte localization to peripheral lymph nodes but did reduce lymphocyte accumulation during long-term migration assays. Treatment with SU5416 also induced severe loss of double-positive thymocytes resulting in thymic atrophy and a reduction in peripheral B cells. Furthermore, immune responses following immunization were reduced in mice treated with SU5416. Findings of thymic atrophy and reduced weight gain during SU5416 treatment suggested elevated corticosterone levels. Indeed, a significant 5-fold increase in serum corticosterone was found 4 hours after treatment with SU5416. Importantly, adrenalectomy negated the effects of SU5416 treatment on primary immune tissues, and partial reversal of SU5416-induced changes was observed following blockade of glucocorticoid receptors. SU5416 has been reported to inhibit the activation of latent transforming growth factor (TGF)-β, a cytokine involved in the regulation of glucocorticoid release by the adrenal glands. Interestingly, treatment with a TGF-β receptor inhibitor, showed a similar phenotype as SU5416 treatment, including elevated serum corticosterone levels and thymic atrophy. Therefore, these results suggest that SU5416 induces glucocorticoid release directly from the adrenal glands, possibly by inhibition of TGF-β activation