Inflammation & Allergy-Drug Targets (v.10, #6)

Commonalities and Differences Between Crohn’s Disease and Ulcerative Colitis: The Genetic Clues to their Interpretation by Giovanni C. Actis, Rinaldo Pellicano, Sonia Tarallo, Floriano Rosina (447-454).
Traditional knowledge of clinical, laboratorial, and endoscopic orders regarding ulcerative colitis and Crohn’sdisease has begun to be implemented by the revolutionary data from genetic studies. Eversince many decades ago it hasbeen clear that Inflammatory bowel diseases are complex multifactorial disorders wherein gut-confined and/orenvironmental factors must synergize with genetic components to effect the full-blown disorder. The sequencing of thehuman genome and the generation of public resources of single nucleotide polymorphisms permitted the conduction ofpowerful population based genome-wide association studies. The latter have increased the number of the identifiedsusceptibility loci to 99. In this review we touched on two pathways that make true susceptibility genes for Inflammatorybowel diseases; gene loci that confer specific risk for ulcerative colitis and Crohn’s disease were discussed in detail.

Damnacanthal-Induced Anti-Inflammation is Associated with Inhibition of NF-κB Activity by Thararat Nualsanit, Pleumchitt Rojanapanthu, Wandee Gritsanapan, Thiwanporn Kwankitpraniti, Kyung-Won Min, Seung Joon Baek (455-463).
Morinda citrifolia L. (Rubiaceae), commonly called noni, is a traditional folk medicinal plant with a longhistory of use for several diseases. Its anti-inflammation activity has been proposed, but detailed knowledge of this antiinflammationmechanism remains unclear. Here, we investigated the effects of noni extract and its major bioactivecomponent damnacanthal on anti-inflammation in vivo as well as in vitro. Our data demonstrate that noni extract and itsbioactive component damnacanthal exhibit suppression of inflammation as evidenced by the suppression of paw and earedema in rats and mice, and down-regulation of lipopolysaccharide-induced nuclear factor-κB (NF-κB) activity,respectively. As a result, the expression of pro-cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase(iNOS) were suppressed in the presence of damnacanthal. These results provide a potential use of damnacanthal in thetreatment of inflammatory-related diseases.

Impact of Sphingosine Kinase on Inflammatory Pathways in Fibroblast- Like Synoviocytes by DeAnna A. Baker, Lina M. Obeid, Gary S. Gilkeson (464-471).
Sphingolipids are mediators of inflammation; changes in their cellular concentration modulate specific cellularfunctions. Investigations of sphingosine kinases (SphK) and sphingosine 1 phosphate (S1P) in TNF.. driven murinemodels of rheumatoid arthritis (RA), identified SphK/S1P as important intermediaries in TNFα mediated synovial proinflammatorypathways. Fibroblast-like synoviocytes (FLS) are key contributors to RA pathogenesis and express bothSphK 1 and 2. To pinpoint the mechanisms of SphK effects in the inflammatory response of murine FLS in vitro, wederived SphK1 null (SphK1-/-) FLS and SphK1 wild-type (SphK1+/+) FLS from the knee joints of B6 mice. Significantlyless MMP1a and IL-6 were produced by mTNFα-stimulated SphK1-/- FLS versus SphK1+/+ FLS. Trends toward lessPGE2 as well as activated, ERK 1/2 and STAT3 were present in SphK1-/- FLS versus SphK1+/+ FLS. Thus geneticinhibition of SphK1 activity resulted in decreased expression of inflammatory mediators and decreased activation ofinflammatory pathways in TNFα stimulated murine FLS. This decreased inflammatory phenotype in FLS lacking SphK1activity is consistent with the attenuated TNF-α-driven arthritis in vivo in SphK1 deficient mice and adds to theunderstanding of the mechanistic role of SpK1/S1P in rheumatoid arthritis. Thus, specific therapeutic can be targeted withSphK inhibitors in rheumatoid arthritis.

The Clinical Stage of Allergic Rhinitis is Correlated to Inflammation as Detected by Nasal Cytology by Matteo Gelardi, Cristoforo Incorvaia, Maria Luisa Fiorella, Paolo Petrone, Nicola Quaranta, Cosimo Russo, Paola Puccinelli, Ilaria Dell’Albani, Gian Galeazzo Riario-Sforza, Eleonora Cattaneo, Gianni Passalacqua, Franco Frati (472-476).
Allergic rhinitis (AR) is the most common allergic disease. The Allergic Rhinitis and its Impact on Asthma(ARIA) guidelines classify AR according to its duration and severity and suggest recommended treatments, but there isevidence that these guidelines are insufficiently followed. Considering the validity of histopathological data, physiciansare more likely to be persuaded by such information on AR. Thus, we attempted to define the severity of AR by nasalcytology on the basis of the ARIA classification. We examined 64 patients with AR caused by sensitization to grasspollen. We clinically defined AR according to the ARIA classification and performed nasal cytology by Rhino-probesampling, staining and reading by optical microscopic observation. Clinically, 22 (34.4%), 21 (32.8%), 10 (15.6%), and11 (17.2%) patients had mild intermittent, moderate-to-severe intermittent, mild persistent, and moderate-to-severepersistent AR, respectively. Nasal cytology detected neutrophils in 49 patients, eosinophils in 41 patients, mast cells in 21patients, and lymphocytes or plasma cells in 28 patients. The patients with moderate-to-severe AR had significantly moremast cells and lymphocytes/ plasma cells than those with mild AR. Our findings demonstrate that the ARIA classification of AR severity is associated with different cell counts in nasalcytology; especially, moderate-to-severe AR shows significantly increased counts of mast cells and lymphocyte or plasmacells. The ease of performing nasal cytology ensures is feasibility as an office AR diagnostic procedure for primary carephysicians, able to indicate when anti-inflammatory treatments, such as intranasal corticosteroids and subcutaneous orsublingual allergen immunotherapy, are needed.

The barrier abnormality, a loss-of-function mutation in the gene encoding filaggrin (FLG), which is linked tothe incidence of atopic dermatitis (AD), is a recently discovered but important factor in the pathogenesis of AD. Toinvestigate this issue in greater detail, mice that have a genetic defect (FLG) in barrier function will provide a model ofAD closer to the human disease. Flaky tail (Flgft) mice, essentially deficient in filaggrin, recently have been introduced toinvestigate the role of filaggrin on AD. These mice showed eczematous skin lesion in the steady state in line withincreased of total IgE and Th17 expression in the skin. There is also an altered skin barrier function as a key element ofAD either outside-to-inside barrier function or vice versa in Flgft mice. Moreover, like human AD, these mice showedenhanced percutaneous allergen priming or response to cutaneous stimulants. Application of mite allergen in Flgft mice,even without prior barrier disruption, remarkably enhanced both the clinical manifestations and the laboratory findingsthat correspond to indicators of human AD. These features of Flgft mice allow us to investigate further the role of filaggrinin AD, and the knowledge obtained using these mice will be quite useful to develop a new therapeutic target for AD.

The Pathology and Immunology of Atopic Dermatitis by Saifur Rahman, Mary Collins, Cara M. M. Williams, Hak-Ling Ma (486-496).
Atopic dermatitis (AD) is a pruritic chronic inflammatory disease of the skin that is triggered by an underlyingcomplicated interplay between the genetics of the individual and stimulation by allergens. Patients with AD demonstratecompromised barrier function that leads to activation of keratinocytes and immune cells which favor a strong Th2 bias. Asa result of this immunological bias such patients also suffer from secondary pathogenic infections. A wide array ofcytokines and chemokines interact to yield symptoms characteristic of AD. In addition, the involvement of differentimmunological cell types compounds our difficulty in understanding its immunopathogenesis. The use of various mousemodels and transgenics has allowed us to intricately examine the functioning of the various molecules identified to play arole in AD. Such mouse models have also aided in the testing and development of various therapeutics for AD. Thisreview is focused on examining the various factors contributing to the pathogenesis and exacerbation of AD as well ascurrent treatments for AD. There is scope for improving the therapy of AD patients and thereby allowing them a betterquality of life.

Aflibercept (VEGF-TRAP): The Next Anti-VEGF Drug by Michael W. Stewart (497-508).
The inflammatory cytokine, vascular endothelial growth factor (VEGF), plays a central role in human growthand development, and vascular maintenance. VEGF mediated angiogenesis is essential for tumor growth, as well asexudative age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity, all of whichare characterized by abnormal neovascularization. Ischemia and inflammation also lead to VEGF-mediated breakdown ofthe blood-retinal barrier, which causes vision diminishing macular edema. To combat these effects, anti-VEGF drugs(antibodies, aptamers, and tyrosine kinase inhibitors) have been developed for both systemic and local (intraocular) use.The next drug to receive regulatory approval will probably be aflibercept (VEGF-Trap), a fusion protein with high VEGFaffinity attributed to binding sequences from the native receptors VEGFR1 and VEGFR2. Aflibercept monotherapysignificantly reduces tumor growth and extends survival in several orthotropic animal models, and has both prevented andreduced the growth of experimental choroidal neovascularization. Ongoing phase III trials are evaluating the effectivenessof aflibercept combined with chemotherapy in patients with advanced carcinomas. The phase III VELOUR trialdetermined that patients receiving aflibercept with irinotecan/5-FU as second line chemotherapy for metastatic colorectalcancer experienced extended progression free survival and overall survival. Intravitreal aflibercept improved visual acuityin patients with exudative age-related macular degeneration and was non-inferior to standard therapy (ranibizumab).Ongoing phase III trials are investigating the use of aflibercept for retinal vein occlusions and diabetic macular edema. Aregulatory approval application for use in exudative macular degeneration has been filed, with a decision expected by late2011.

Despite increasing knowledge about molecular pathways in pathogenesis of chronic liver disease, selectivetherapeutic options are scarce, especially in advanced diseases characterized by scarring of the liver (termed fibrosis) oreven complete cirrhosis. Sustained hepatic inflammation as a result to various types of injury (e.g., hepatitis C, nonalcoholicsteatohepatitis) is generally accepted to represent the key prerequisite for fibrogenesis. Liver inflammation ischaracterized by an activation of distinct chemokine pathways in the liver and the circulation allowing distinct immunecell populations to enter the liver via sinusoids and postsinusoidal venules. Recent investigations have shed light on theintimate interactions between the fibrogenic hepatic stellate cell (HSC) and infiltrating immune cells, whichfundamentally drive liver scarring. Experimental fibrosis and inflammation models have demonstrated that disruption ofchemokine pathways such as CCL2 (MCP-1) or its receptor CCR2, CCL5 (RANTES) or CCR1 / CCR5 and others mayefficiently prevent collagen deposition, by targeting monocytes and macrophages, T-cell populations or NKT cells.However, immigration of certain mononuclear cells may even be beneficial in the course of fibrosis. Infiltrating NK cellsand monocyte-derived macrophage subsets can promote resolution of extracellular matrix. This emphasizes that hepaticfibrosis is not a unidirectional process, but can be reverted up to a certain point. The present review aims at summarizingthe contribution of immune cell infiltration as well as related chemokine systems to experimental liver fibrosis and willdiscuss possible therapeutic applications in humans, with a special emphasis on the monocyte/macrophage lineage andtheir related chemokine pathways.