Role of complement in in vitro and in vivo lung inflammatory reactions

Complement is one of the integral buttresses of the inflammatory response. In addition to host defense activities, proinflammatory properties of several complement components are described. This overview elucidates the role of complement in inflammatory reactions in vitro and in vivo, focusing on the complement activation products, C5a, and the membrane attack complex, C5b‐9. Using several approaches, the impact of these complement components in mechanisms relevant to neutrophil recruitment is emphasized. In addition, the participation of complement in endothelial superoxide generation and its essential requirement for full expression of lung injury is demonstrated, as are the involved intracellular signal transduction pathways. Understanding the mechanisms of complement‐induced proinflammatory effects may provide a basis for future therapeutic blockade of complement and/or its activation products. J. Leukoc. Biol. 64: 40–48; 1998.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142061/1/jlb0040.pd

Endogenous regulation of the acute inflammatory response

The acute inflammatory response has been triggered in rat lungs by deposition of IgG immune complexes. The inflammatory reaction triggered is highly tissue damaging and requires activation of NF-κB with ensuing generation of chemokines and cytokines. Endogenous generation of IL-10 and IL-13 as well as secretory leukocyte protease inhibitor (SLPI), significantly regulates this inflammatory response. IL-10 and IL-13 attenuate NF-κB activation by interfering with breakdown of IκBα, while SLPI likewise suppresses NF-κB activation, but by interfering with breakdown of IκBβ. Antibody induced blockade of IL-10, IL-13 or SLPI enhances NF-κB activation in lung and exacerbates the lung inflammatory response and injury. These data indicate that endogenous IL-10, IL-13 and SLPI are important regulators of the inflammatory response by reducing gene activation with resultant generation of peptide mediators/cytokines and chemokines.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45338/1/11010_2004_Article_407649.pd

Experimental design of complement component 5a‐induced acute lung injury (C5a‐ALI): a role of CC‐chemokine receptor type 5 during immune activation by anaphylatoxin

Excessive activation of the complement system is detrimental in acute inflammatory disorders. In this study, we analyzed the role of complement‐derived anaphylatoxins in the pathogenesis of experimental acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in C57BL/6J mice. Intratracheal administration of recombinant mouse complement component (C5a) caused alveolar inflammation with abundant recruitment of Ly6‐G+CD11b+ leukocytes to the alveolar spaces and severe alveolar‐capillary barrier dysfunction (C5a‐ALI; EC50[C5a] = 20 ng/g body weight). Equimolar concentrations of C3a or desarginated C5a (C5adesArg) did not induce alveolar inflammation. The severity of C5a‐ALI was aggravated in C5‐deficient mice. Depletion of Ly6‐G+ cells and use of C5aR1‐/‐ bone marrow chimeras suggested an essential role of C5aR1+ hematopoietic cells in C5a‐ALI. Blockade of PI3K/Akt and MEK1/2 kinase pathways completely abrogated lung injury. The mechanistic description is that C5a altered the alveolar cytokine milieu and caused significant release of CC‐chemokines. Mice with genetic deficiency of CC‐chemokine receptor (CCR) type 5, the common receptor of chemokine (C‐C motif) ligand (CCL) 3, CCL4, and CCL5, displayed reduced lung damage. Moreover, treatment with a CCR5 antagonist, maraviroc, was protective against C5a‐ALI. In summary, our results suggest that the detrimental effects of C5a in this model are partly mediated through CCR5 activation downstream of C5aR1, which may be evaluated for potential therapeutic exploitation in ALI/ARDS.—Russkamp, N. F., Ruemmler, R., Roewe, J., Moore, B. B., Ward, P. A., Bosmann, M. Experimental design of complement component 5a‐induced acute lung injury (C5a‐ALI): a role of CC‐chemokine receptor type 5 during immune activation by anaphylatoxin. FASEB J. 29, 3762‐3772 (2015). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154372/1/fsb2029009014.pd

Turbulent Molecular Cloud Cores: Rotational Properties

The rotational properties of centrally condensed, turbulent molecular cloud cores with velocity fields that are characterized by Gaussian random fields are investigated. It is shown that the observed line width-size relationship can be reproduced if the velocity power spectrum is a power-law with P(k)=k**n and n=-3 to -4. The line-of-sight velocity maps of these cores show velocity gradients that can be interpreted as rotation. For n=-4, both, the deduced values of the angular velocity Omega=1.6 km/s/pc * (R/0.1 pc)**0.5 and the scaling relations between Omega and the core radius R are in very good agreement with the observations. As a result of the dominance of long wavelength modes, the cores also have a net specific angular momentum with an average value of j=7*(10**20)*(R/0.1 pc)**(1.5) cm**2/s with a large spread. Their internal dimensionless rotational parameter is beta=0.03, independent of the scale radius R. In general, the line-of-sight velocity gradient of an individual turbulent core does not provide a good estimate of its internal specific angular momentum. We find however that the distribution of the specific angular momenta of a large sample of cores which are described by the same power spectrum can be determined very accurately from the distribution of their line-of-sight velocity gradients Omega using the simple formula j=p*Omega*R*R where p depends on the density distribution of the core and has to be determined from a Monte-Carlo study. Our results show that for centrally condensed cores the intrinsic angular momentum is overestimated by a factor of 2-3 if p=0.4 is used.Comment: 23 pages, 7 figures, Astrophysical Journal, in pres

A reconfiguration of the sex trade: how social and structural changes in eastern Zimbabwe left women involved in sex work and transactional sex more vulnerable

Understanding the dynamic nature of sex work is important for explaining the course of HIV epidemics. While health and development interventions targeting sex workers may alter the dynamics of the sex trade in particular localities, little has been done to explore how large-scale social and structural changes, such as economic recessions–outside of the bounds of organizational intervention–may reconfigure social norms and attitudes with regards to sex work. Zimbabwe’s economic collapse in 2009, following a period (2000–2009) of economic decline, within a declining HIV epidemic, provides a unique opportunity to study community perceptions of the impact of socio-economic upheaval on the sex trade. We conducted focus group discussions with 122 community members in rural eastern Zimbabwe in January-February 2009. Groups were homogeneous by gender and occupation and included female sex workers, married women, and men who frequented bars. The focus groups elicited discussion around changes (comparing contemporaneous circumstances in 2009 to their memories of circumstances in 2000) in the demand for, and supply of, paid sex, and how sex workers and clients adapted to these changes, and with what implications for their health and well-being. Transcripts were thematically analyzed. The analysis revealed how changing economic conditions, combined with an increased awareness and fear of HIV–changing norms and local attitudes toward sex work–had altered the demand for commercial sex. In response, sex work dispersed from the bars into the wider community, requiring female sex workers to employ different tactics to attract clients. Hyperinflation meant that sex workers had to accept new forms of payment, including sex-on-credit and commodities. Further impacting the demand for commercial sex work was a poverty-driven increase in transactional sex. The economic upheaval in Zimbabwe effectively reorganized the market for sex by reducing previously dominant forms of commercial sex, while simultaneously providing new opportunities for women to exchange sex in less formal and more risky transactions. Efforts to measure and respond to the contribution of sex work to HIV transmission need to guard against unduly static definitions and consider the changing socioeconomic context and how this can cause shifts in behavior

In Vivo Recruitment of Neutrophils: Consistent Requirements for L-Arginine and Variable Requirements for Complement and Adhesion Molecules

The current studies examined the mechanisms of neutrophil recruitment into the rat peritoneal cavity following injection of glycogen and into rat lungs following alveolar deposition of IgA immune complexes or airway instillation of phorbol ester (PMA). Unexpectedly, in each model a requirement for L-arginine for neutrophil recruitment was demonstrated, since administration of the L-arginine analogue, N G -monomethyl L-arginine acetate (L-NMA), greatly reduced neutrophil accumulation as assessed by quantitation of neutrophils in peritoneal exudates and bronchoalveolar lavage fluids, and by lung myeloperoxidase content. In the case of IgA immune complex deposition, lung recruitment of neutrophils was also suppressed by soluble recombinant human complement receptor-1 (sCR1) and antibody to CD18 but not by antibody to E-selectin. In contrast, neutrophil accumulation following airway instillation of PMA exhibited, surprisingly, no requirement for complement but requirements for both E-selectin and CD18. These data demonstrate variable requirements for complement, E-selectin and CD18 but a consistent requirement for L-arginine for neutrophil recruitment. These findings provide evidence suggesting that L-arginine or its derivatives regulate neutrophil recruitment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44519/1/10753_2004_Article_417585.pd

Socioeconomic consequences of the COVID‐19 pandemic for people who use drugs

The COVID-19 pandemic triggered widespread socioeconomic hardship, disproportionately impacting disadvantaged populations. People who use illicit drugs are more likely to experience unemployment, homelessness, criminal justice involvement and poorer health outcomes than the general community, yet little is known about the socioeconomic impacts of the pandemic on their lives. To address this gap in the literature, we conducted in-depth interviews with 76 participants from two cohort studies of people who use illicit drugs (people who inject drugs and/or use methamphetamine) in Victoria, Australia. Findings support claims that pandemic-related Social Security supplementary payments and initiatives to reduce homelessness, although not systemically transforming people's lives, produced temporary relief from chronic socioeconomic hardship. Results also indicate how temporary interruptions to drug supply chains inflated illicit drug prices and produced adverse consequences such as financial and emotional stress, which was exacerbated by drug withdrawal symptoms for many participants. Furthermore, increased community demand for emergency food and housing support during the pandemic appeared to reduce participants' access to these services. Our findings about the unintended consequences of pandemic responses on the socioeconomic lives of a group of people who use illicit drugs provide insights into and opportunities for policy reform to redress their entrenched disadvantage

Different bacterial gene expression patterns and attenuated host immune responses are associated with the evolution of low-level vancomycin resistance during persistent methicillin-resistant Staphylococcus aureus bacteraemia

BACKGROUND: Low-level vancomycin resistance in Staphylococcus aureus (vancomycin-intermediate S. aureus (VISA) and hetero-VISA [hVISA]) emerges during persistent infection and failed vancomycin therapy. Up-regulation of genes associated with the "cell wall stimulon" and mutations in the vraSR operon have both been implicated in the development of resistance, however the molecular mechanisms of resistance are not completely understood. To further elucidate the mechanisms leading to resistance transcriptome comparisons were performed using multiple clinical pairs of vancomycin-susceptible S. aureus (VSSA) and hVISA/VISA (n = 5), and three VSSA control pairs from hospitalized patients with persistent bacteraemia that did not develop hVISA/VISA. Based on the transcriptome results multiple genes were sequenced and innate immune system stimulation was assessed in the VSSA and hVISA/VISA pairs. RESULTS: Here we show that up-regulation of vraS and the "cell wall stimulon" is not essential for acquisition of low-level vancomycin resistance and that different transcriptional responses occur, even between closely related hVISA/VISA strains. DNA sequencing of vraSR, saeSR, mgrA, rot, and merR regulatory genes and upstream regions did not reveal any differences between VSSA and hVISA/VISA despite transcriptional changes suggesting mutations in these loci may be linked to resistance in these strains. Enhanced capsule production and reduced protein A expression in hVISA/VISA were confirmed by independent bioassays and fully supported the transcriptome data. None of these changes were observed in the three control pairs that remained vancomycin-susceptible during persistent bacteremia. In a macrophage model of infection the changes in cell surface structures in hVISA/VISA strains were associated with significantly reduced NF-kappaB activation resulting in reduced TNF-alpha and IL-1beta expression. CONCLUSION: We conclude that there are multiple pathways to low-level vancomycin resistance in S. aureus, even among closely related clinical strains, and these can result in an attenuated host immune response. The persistent infections associated with hVISA/VISA strains may be a consequence of changes in host pathogen interactions in addition to the reduced antibiotic susceptibility