Complement C5 and Early Oxygen Kinetics during Murine Sepsis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74696/1/j.aem.2004.10.025.pd

Attenuation of IgG immune complex‐induced acute lung injury by silencing C5aR in lung epithelial cells

Acute lung injury (ALI) in mouse lung occurs after distal airway deposition of IgG immune complexes (IgGICs), resulting in a breakdown of the vascular‐airway barrier, causing intrapulmonary edema, hemorrhage, and accumulation of neutrophils [polymorphonuclear leukocytes (PMNs)] in the alveolar compartment, these changes being complement (C5a) and C5a receptor (C5aR) dependent. In this ALI model, C5aR expression (protein) was found to occur on upper (bronchial) and lower (alveolar) airway epithelial cells. An adenovirus construct (siRNA) was used to silence mRNA for C5aR in the lung. Under such conditions, C5aR protein was markedly reduced on lung epithelial cells, resulting in much reduced leakage of albumin into the lung, diminished buildup of PMNs, and lower levels of proinflammatory mediators in bronchoalveolar lavage fluids. These studies indicate that bronchial and alveolar epithelial cell C5aR is up‐regulated and greatly contributes to inflammation and injury in the lung. The use of siRNA administered into the airways avoids systemic suppression of C5aR, which might compromise innate immunity. It is possible that such an intervention might be employed in humans with ALI or acute respiratory distress syndrome as well as in upper‐airway inflammatory diseases, such as chronic obstructive pulmonary disease and asthma, where there is evidence for complement activation and buildup of PMNs.—Sun, L., Guo, R.‐F., Gao, H., Sarma, J. V., Zetoune, F. S., Ward, P. A. Attenuation of IgG immune complex‐induced acute lung injury by silencing C5aR in lung epithelial cells. FASEB J. 23, 3808–3818 (2009). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154350/1/fsb2fj09133694.pd

An essential role for Stat3 in regulating IgG immune complex‐induced pulmonary inflammation

Growing evidence suggests that transcription factor signal transducer and activator of transcription (Stat) 3 may play an important regulatory role during inflammation. However, the function of Stat3 in acute lung injury (ALI) is largely unknown. In the current study, by using an adenoviral vector expressing a dominant‐negative Stat3 isoform (Ad‐Stat3‐EVA), we determined the role of Stat3 in IgG immune complex (IC)‐induced inflammatory responses and injury in the lung from C57BL/6J mice. We show that IgG IC‐induced DNA binding activity of Stat3 in the lung was significantly inhibited by Stat3‐EVA. We demonstrate that both lung vascular permeability (albumin leak) and lung myeloperoxidase accumulation in the Ad‐Stat‐EVA treated mice were substantially reduced when compared with values in mice receiving control virus (Ad‐GFP) during the injury. Furthermore, intratracheal administration of Ad‐Stat3‐EVA caused significant decreases in the contents of neutrophils, inflammatory cytokines (TNF‐α and IL‐6), chemokines [keratinocyte cell‐derived chemokine, macrophage inflammatory protein (MIP)‐1α, and MIP‐1β], and complement component C5a in bronchoalveolar lavage fluids. Using Stat3‐specific small interfering RNA, we show that knocking down Stat3 expression in alveolar macrophages (MH‐S cells) significantly reduced the production of proinflammatory mediators on IgG IC stimulation. These data suggest that Stat3 plays an essential role in the pathogenesis of IgG IC‐induced ALI by mediating the acute inflammatory responses in the lung and alveolar macrophages.—Tang, H., Yan, C., Cao, J., Sarma, J. V., Haura, E. B., Wu, M., Gao, H. An essential role for Stat3 in regulating IgG immune complex‐induced pulmonary inflammation. FASEB J. 25, 4292–4300 (2011). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154500/1/fsb2fj11187955.pd

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

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

MyD88‐dependent production of IL‐17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway

The interleukin‐17 (IL‐17) family of cytokines plays important roles in innate immune defenses against bacterial and fungal pathogens. While much is known about IL‐17A, much less information is available about the IL‐17F isoform. Here, we investigated gene expression and release of IL‐17F and its regulation by the complement system. IL‐17F was produced in mouse peritoneal elicited macrophages after TLR4 activation by LPS, peaking after 12 h. This effect was completely dependent on the presence of the adaptor protein MyD88. The copresence of the complement activation product, C5a (EC50=10 nM), amplified IL‐17F production via the receptor C5aR. In vitro signaling studies indicated that LPS or C5a, or the combination, caused phosphorylation of Akt occurring at threonine 308 but not at serine 473. Treatment of macrophages with pharmacologic inhibitors of PI3K‐Akt greatly reduced production of IL‐17F as well as mRNA for IL‐17F. In endotoxemia, C5a levels peaked at 6 h, while IL‐17F levels peaked between 6‐12 h. Full in vivo production of IL‐17F during endotoxemia required C5a. A similar result was found in the cecal ligation and puncture sepsis model. These data suggest that maximal production of IL‐17F requires complement activation and presence of C5a.—Bosmann, M., Patel, V. R., Russkamp, N. F., Pache, F., Zetoune, F. S., Sarma, J. V., Ward, P. A. MyD88‐dependent production of IL‐17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway. FASEB J. 25, 4222–4232 (2011). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154335/1/fsb2fj11191205.pd

Upregulation of Phagocyte-Derived Catecholamines Augments the Acute Inflammatory Response

Following our recent report that phagocytic cells (neutrophils, PMNs, and macrophages) are newly discovered sources of catecholamines, we now show that both epinephrine and norepinephrine directly activate NFκB in macrophages, causing enhanced release of proinflammatory cytokines (TNFα, IL-1β, IL-6). Both adrenal-intact (AD+) and adrenalectomized (ADX) rodents were used, because ADX animals had greatly enhanced catecholamine release from phagocytes, facilitating our efforts to understand the role of catecholamines released from phagocytes. Phagocytes isolated from adrenalectomized rats displayed enhanced expression of tyrosine-hydroxylase and dopamine-β-hydroxylase, two key enzymes for catecholamine production and exhibited higher baseline secretion of norepinephrine and epinephrine. The effects of upregulation of phagocyte-derived catecholamines were investigated in two models of acute lung injury (ALI). Increased levels of phagocyte-derived catecholamines were associated with intensification of the acute inflammatory response, as assessed by increased plasma leak of albumin, enhanced myeloperoxidase content in lungs, augmented levels of proinflammatory mediators in bronchoalveolar lavage fluids, and elevated expression of pulmonary ICAM-1 and VCAM-1. In adrenalectomized rats, development of ALI was enhanced and related to α2-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFκB and further downstream cytokine production of these cells. In adrenalectomized animals, which have been used to further assess the role of catecholamines, there appears to be a compensatory increase in catecholamine generating enzymes and catecholamines in macrophages, resulting in amplification of the acute inflammatory response via engagement of α2-adrenoceptors

Functions of the complement components C3 and C5 during sepsis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154678/1/fsb2fj08110595.pd

Regulatory effects of interleukin‐11 during acute lung inflammatory injury

The role of interleukin‐11 (IL‐11) was evaluated in the IgG immune complex model of acute lung injury in rats. IL‐11 mRNA and protein were both up‐regulated during the course of this inflammatory response. Exogenously administered IL‐11 substantially reduced, in a dose‐dependent manner, the intrapulmonary accumulation of neutrophils and the lung vascular leak of albumin. These in vivo anti‐inflammatory effects of IL‐11 were associated with reduced NF‐κB activation in lung, reduced levels of tumor necrosis factor α (TNF‐α) in bronchoalveolar lavage (BAL) fluids, and diminished up‐regulation of lung vascular ICAM‐1. It is interesting that IL‐11 did not affect BAL fluid content of the CXC chemokines, macrophage inflammatory protein‐2 (MIP‐2) and cytokine‐inducible neutrophil chemoattractant (CINC); the presence of IL‐11 did not affect these chemokines. However, BAL content of C5a was reduced by IL‐11. These data indicate that IL‐11 is a regulatory cytokine in the lung and that, like other members of this family, its anti‐inflammatory properties appear to be linked to its suppression of NF‐κB activation, diminished production of TNF‐α, and reduced up‐regulation of lung vascular ICAM‐1. J. Leukoc. Biol. 66: 151–157; 1999.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141937/1/jlb0151.pd