Inflammation suppressor genes: please switch out all the lights

An effective immune system requires rapid and appropriate activation of inflammatory mechanisms but equally rapid and effective resolution of the inflammatory state. A review of the canonical host response to gram-negative bacteria, the lipopolysaccharide-Toll-like receptor 4 signaling cascade, highlights the induction of repressors that act at each step of the activation process. These inflammation suppressor genes are characterized by their induction in response to pathogen, typically late in the macrophage activation program, and include an expanding class of dominant-negative proteins derived from alternate splicing of common signaling components. Despite the expanse of anti-inflammatory mechanisms available to an activated macrophage, the frailty of this system is apparent in the large numbers of genes implicated in chronic inflammatory diseases. This apparent lack of redundancy between inflammation suppressor genes is discussed with regard to evolutionary benefits in generating a heterogeneous population of immune cells and consequential robustness in defense against new and evolving pathogens.

Control of ion transport in mammalian airways by protease activated receptors type 2 (PAR-2)

Protease-activated receptors (PARs) are widely distributed in human airways. They couple to G-proteins and are activated after proteolytic cleavage of the N terminus of the receptor. Evidence is growing that PAR subtype 2 plays a pivotal role in inflammatory airway diseases, such as allergic asthma or bronchitis. However, nothing is known about the effects of PAR-2 on electrolyte transport in the native airways. PAR-2 is expressed in airway epithelial cells, where they are activated by mast cell tryptase, neutrophil proteinase 3, or trypsin. Recent studies produced conflicting results about the functional consequence of PAR-2 stimulation. Here we report that stimulation of PAR-2 receptors in mouse and human airways leads to a change in electrolyte transport and a shift from absorption to secretion. Although PAR-2 appears to be expressed on both sides of the epithelium, only basolateral stimulation results in inhibition of amiloride sensitive Na+ conductance and stimulation of both luminal Cl- channels and basolateral K+ channels. The present data indicate that these changes occur through activation of phospholipase C and increase in intracellular Ca2+, which activates basolateral SK4 K+ channels and luminal Ca2+-dependent Cl- channels. In addition, the present data suggest a PAR-2 mediated release of prostaglandin E2, which may contribute to the secretory response. In conclusion, these results provide further evidence for a role of PAR-2 in inflammatory airway disease: stimulation of these receptors may cause accumulation of airway surface liquid, which, however, may help to flush noxious stimuli away from the affected airways. ©2005 FASEB

NF-gamma B - a target in the inflammation of bone destruction

NF-kappaB activation is associatied with the inflammation of bone destruction and certain cancers. The NEMO (NF-kB essential modulator)-binding domain (NBD) protein inhibits the activation of NF-kappaB. Cellular studies have shown that the NBD protein inhibits osteoclastogenesis. Mimicking infection with a lipopolysaccharide injection in mice resulted in activated osteoclasts and reduced bone mineral density. These responses are inhibited with the NBD peptide. In a mouse model of rheumatoid arthritis, collagen-induced arthritis, treatment with the NBD protein delayed the onset, lowered the incidence and decreased the severity of the arthritis. NF-kappaB is a target in the inflammation associated with bone destruction. A key issue is whether or not this important transcription factor can be inhibited without causing excessive adverse effects and/or toxicity.

Drugs to treat inflammation: A historical introduction

Drugs to treat inflammation are discussed under the following headings: (1) random discoveries covering copper, salicylates, heterocyclic diones, ACTH, adrenal steroids and disease-modifying agents (DMARDs); these include Au(I)-thiolates, chloroquine, and hydroxychloroquine, minocycline, cyclosporin, salazopyrine, D-penicillamine and methotrexate; (2) programmed NSAID developments covering salicylates and fenamates, arylalkanoates, diones, non-acidic NSAIDs, clozic, lobenzarit and coxibs; (3) synthetic glucocorticosteroids; and (4) 'Biologicals' for neutralising pro-inflammatory cytokines. Clinical problems are highlighted, particularly unacceptable side-effects affecting the GI tract, skin, liver, etc. that caused many drugs to be withdrawn. Drug combinations may overcome some of these problems. The bibliography has selected reviews and monographs covering 50 years of publications.

Challenge-induced plasma exudation and mucinous secretion in human airways

Secretion of mucins and exudation of plasma are distinct processes of importance to innate immunity and inflammatory disease. Yet, little is known about their relation in human airways. The objective of the present study was to use the human nasal airway to determine mucinous secretion and plasma exudation in response to common challenge agents and mediators. Ten healthy volunteers were subjected to nasal challenge-lavage procedures. Thus, the nasal mucosa was exposed to increasing doses of histamine (40 and 400 mu g ml(-1)), methacholine (12.5 and 25 mg) and capsaicin (30 and 300 ng ml(-1)). Fucose was selected as a global marker of mucinous secretion and alpha(2)-macroglobulin as an index of exudation of bulk plasma. All challenge agents increased the mucosal output of fucose to about the same level (P < 0.01-0.05). Once significant secretion had been induced the subsequently increased dose of the challenge agent, in the case of histamine and methacholine, failed to further increase the response. Only histamine increased the mucosal output of alpha(2)-macroglobulin (P < 0.01). We conclude that prompt but potentially rapidly depleted mucinous secretion is common to different kinds of airway challenges, whereas inflammatory histamine-type mediators are required to produce plasma exudation. Along with the acknowledged secretion of mucins, a practically non-depletable, pluripotent mucosal output of plasma emerges as an important component of the innate immunity of human airways.

Secretoneurin is released into human airways by topical histamine but not capsaicin

Background: The neuropeptide secretoneurin, with potential relevance to leukocyte trafficking, is present in nerves of the nasal mucosa in allergic rhinitis and may be released in response to allergen and histamine exposure. There is no information on the occurrence and mechanisms of release of secretoneurin in healthy human airways. Methods: The presence of secretoneurin in nasal biopsies and its release in response to nasal capsaicin and histamine challenges were examined. Symptoms and lavage fluid levels of fucose were recorded as markers of effects in part produced by neural activity. Bronchial histamine challenges followed by sputum induction and analysis of secretoneurin were also carried out. Results: Nerves displaying secretoneurin immunoreactivity abounded in the nasal mucosa. Nasal capsaicin challenge produced local pain (P < 0.05) and increased the levels of fucose (P < 0.05), but failed to affect the levels of secretoneurin. Nasal histamine challenge produced symptoms (P < 0.05) and increased the mucosal output of secretoneurin (P < 0.05) and fucose (P < 0.05). Bronchial histamine challenge increased the sputum levels of secretoneurin (P < 0.05). Conclusions: We conclude that secretoneurin is present in healthy human airways and that histamine evokes its release in both nasal and bronchial mucosae. The present observations support the possibility that secretoneurin is involved in histamine-dependent responses of the human airway mucosa.

S100A8 chemotactic protein is abundantly increased, but only a minor contributor to LPS-induced, steroid resistant neutrophilic lung inflammation in vivo

Neutrophilic lung inflammation is an essential component of host defense against diverse eukaryotic and prokaryotic pathogens, but in chronic inflammatory lung diseases, such as chronic obstructive lung disease (COPD), severe asthma, cystic fibrosis, and bronchiolitis, it may damage the host. Glucocorticosteroids are widely used in these conditions and in their infectious exacerbations; however, the clinical efficacy of steroids is disputed. In this study, we used a proteomic approach to identify molecules contributing to neutrophilic inflammation induced by transnasal administration of lipopolysaccharide (LPS) that were also resistant to the potent glucocorticosteroid dexamethasone (Dex). We confirmed that Dex was biologically active at both the transcript (suppression of GM-CSF and TNFalpha transcripts) and protein levels (induction of lipocortin) and used 2D-PAGE/MALDI-TOF to generate global expression profiles, identifying six LPS-induced proteins that were Dex resistant. Of these, S100A8, a candidate neutrophil chemotactic factor, was profiled in detail. Steroid refractory S100A8 expression was highly abundant, transcriptionally regulated, secreted into lung lavage fluid and immunohistochemically localized to tissue infiltrating neutrophils. However, in marked contrast to other vascular beds, neutralizing antibodies to S100A8 had only a weak anti-neutrophil recruitment effect and antibodies against the related S100A9 were ineffective. These data highlight the need for extensive in vivo profiling of proteomically identified candidate molecules and demonstrates that S100A8, despite its abundance, resistance to steroids and known chemotactic activity, is unlikely to be an important determinant of LPS-induced neutrophilic lung inflammation in vivo.

Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal(-/-) mice

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell. The downstream metabolites of these compounds serve as hormonal ligands for nuclear receptors and transcription factors. Genetic ablation of the lal gene in the mouse caused malformation of macrophages and inflammation-triggered multiple pathogenic phenotypes in multiple organs. To assess the relationship between macro phages and lal(-/-) pathogenic phenotypes, a macrophage-specific doxycycline-inducible transgenic system was generated to induce human LAL (hLAL) expression in the lal(-/-) genetic background under control of the 7.2-kb c-fins promoter/intron2 regulatory sequence. Doxycycline-induced hLAL expression in macrophages significantly ameliorated aberrant gene expression, inflammatory cell (neutrophil) influx, and pathogenesis in multiple organs. These studies strongly support that neutral lipid metabolism in macrophages contributes to organ inflammation and pathogenesis.

Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: A meta-analysis of individual patient data

Background & Aims: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. Methods: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. Results: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in :1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in :142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. Conclusions: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.