Inflammation & Allergy-Drug Targets (v.10, #4)

Editorial from Editor-in-Chief by Kurt S. Zaenker (226-226).
The journal “Inflammation & Allergy - Drug Targets” has become over the years one of the leading journals in the specializedfield of inflammation, allergy and identification of appropriate molecular targets which can be addressed by well known ornewly launchend drugs for the benefit of patients. The journal paves scientifically the road for new concepts and ideas and allthe people responsible for the success of the journal are prepared that it is time to think outside the box of solely genetic orconventional scientific education - in a time where we are aiming towards personalized medicine and re-think about theconcept of epigenetic, which choreographs the interface between the genetic make-up and the environment of a human being.Scientific journals provide a foundation for scientific progress. Limitations of journal space affect the marketplace for ideas.Space is allocated primarily by the decisions of peer reviews. It is known that peer rating do not always correlate well with thenumber of citations that the papers eventually receive. This suggests that existing policies are not adequate for identifyingpapers that will be important for further and future research. Importance has many dimensions:i) is the problem novel and important and for whom? ii) do the results add significant news to what is known?iii) will the paper affect decision-making for future research or operationally speaking, for physicians, health care providers,public health organizations or even for the patient. In their attempts to gain status, journals frequently depart fromproblems that might contribute to decisions-making.To obtain a better assessment of the importance of a problem, as Editor-in-Chief, I strongly encourage authors to submit papershaving already addressed molecular or clinical problems and which have been previously published in this journal in order toshow now and timely the successful follow-up or even stagnation, focused either on an improved value of the scientificknowledge, competence and eduction or regarding a better clinical outcome. This does not mean to come back what has beenreferred to as writing the “least publishable unit”, where the reader is forced to use different journals to obtain sufficient detailsof solving a problem or difficulties.Former authors are invited to report on the objective achievments over the years in their fields of interest in order to keep thereaders up to “the-state-of-the-art”.Furthermore, when we are talking about the objectives and goals of a scientific journal, these tend to be embedded with alreadytaken for granted assumptions or working hypothesis. However, implicit importance is what an individual as scientist, what ascientific team and the scientific community is already thinking - for the benefit of the education of the members of her/hisscientific community, for the increasing knowledge within a society, and even more important, for the benefit of a human beingas a patient.Scientific publishing must not become a poor substitute for its best vision, but should be provocative and vivid. Therefore, wedecided to publish a review by Oellers et al. concerning immunological processes within the vitreoretinal compartment.Generally, the eye is regarded as immune incompetent, however, this review clearly states the cellular activities of the immunesystem in the pathogenesis of e.g. acute macular degeneration, glaucoma, diabetic retinopathy and, of course, uveitis.Furthermore, aging of the retina is accompanied by many inflammatory processes.As Editor-in-Chief, I very much envisage that this review will deserve within the ophthalmology societies worldwide reading,discussing pro and cons and, ultimately, in citing priority we are looking for. Hopefullly, this review might pave a novel road tounderstand the largely ignored immune competence of the eye.Scientists are privileged to use their senses, observations and experiments to describe and explain natural phenomena, however,in a sense as Georg Bernard Shaw once has written: “The reasonable man adapts himself to the world; the unreasonable onepersists in trying to adapt the world to himself. Therefore, all progress depends on the unreasonable man”.Therefore, let us publish further papers, views, comments and scientific conflicts by unreasonable scientific authors.

Inflammation, as defined by Stedman’s concise medical dictionary, is “a fundamental, stereotyped complex of cytologic andchemical reactions that occur in affected blood vessels and adjacent tissues in response to an injury or abnormal stimulationcaused by a physical, chemical, or biologic agent” [1]. It is well established that inflammatory response is a feature andpathophysiological mechanism of many diseases including infectious diseases, cardiovascular diseases (CVDs), acute kidneyinjury (AKI), inflammatory bowel diseases, allergy, asthma and respiratory distress syndrome, etc. Recently, inflammatoryfactors have been emerging as novel biomarkers for the prediction, diagnosis, screening, and monitoring for various diseases.Many of these inflammatory biomarkers are not just by standers, but actually involve the underneath pathogenesis and play afundamental role in the development of diseases.This theme topic issue of the Inflammation Allergy - Drug Targets focuses on recent advances on emerging inflammatorybiomarkers. Distinguished authors including clinical biochemists, physicians and research scientists in the field were invited toreview and summarize several important inflammatory biomarkers for their clinical utility on disease diagnosis andmanagement, and their roles on pathophysiology of diseases. Potential therapies targeting these inflammatory biomarkers werealso incorporated in their discussions.Current evidence suggest that high sensitivity C-reactive protein (hsCRP) is an independent CVD risk factor and themeasurement of hs-CRP is being recommended in men older than 50 years and women older than 60 years of age who are atintermediate risk (10% to 19%) according to their Framingham risk scores and who do not otherwise qualify for lipid-loweringtherapy (i.e., if their LDL-C is less than 3.5 mmol/L) [2]. hsCRP of less than 2 mg/L is also recommended as a secondary(optional) therapeutic target (once low-density lipoprotein cholesterol is at goal) [2]. Maekawa et al. review major relevantfindings associates with the clinical implications of CRP and pentraxin3 (PTX3), which belong to the pentraxins superfamilyinvolving in innate immunity, and their role in CVD [3]. Their discussion indicates that in addition to the significance as aprognostic arm, PTX3 might be cardio- and atheroprotective through the modification of innate immunity and inflammatoryresponse; however, whether CRP function contributes to CVD remains unclear.Compared with many other inflammatory biomarkers, plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) hasdemonstrated a high specificity for vascular inflammation because of the origin source of this enzyme mainly frominflammatory cells in atherosclerotic plaques and its association with LDL, HDL and VLDL. Interestingly, Lp-PLA2 may playas a cardio-protective if associated with HDL, whereas Lp-PLA2 may be pro-athergenic, pro-inflammatory, and pro-apoptoticif the enzyme bound to apolipoprotein-B-containing lipoproteins. Ahmed et al. provide an overview on biochemistry, biologicalfunction, and clinical utility as an independent CVD biomarker of Lp-PLA2 [4]. They are also in favor of the role of Lp-PLA2as a potential pharmacologic therapeutic target for atherosclerosis.Heat shock proteins (Hsps) are highly conserved proteins that protect organisms against deleterious and noxious stimuli orsubsequent injury. Heat shock proteins are well known for their primarily function as molecular chaperones which facilitate thefolding and refolding, assembly and stabilization of other proteins. Recently, Hsps have indicated important regulatory roles inboth innate and acquired immunity and inflammation [5]. Furthermore, Hsp27, Hsp60 and Hsp90 are all found releasing fromcardiomyocytes into circulation after injury and as potential biomarkers for myocardial infraction or heart failure [6-8]. Joneset al. summarize the recent work from their group as well others on Hsps protection against myocardial ischemia andinflammation [9]. They also review their studies on insulin-induced myocardial protection and its realtionship with Hsps. Itappears that Hsps protection on heart and inflammation may be time- and stimulus- dependent through different mechanisms.Once these fundamental processes are well understood, targeted therapeutic intervention may be possible.AKI, the previously so-called acute renal failure, is a common clinical situation with serious consequences in hospitalizedpatients. There is an urgent call for novel biomarkers for the early diagnosis of AKI to expedite appropriate interventions toprevent morbidity and mortality. The current clinically widely used serum creatinine and its derivative estimated glomerularfiltration rate are far from ideal AKI markers in that serum creatinine is only valid for assessment for renal function once itreaches a steady state. Serum creatinine is not very useful for kidney injury for lacking of enough sensitivity and specificity andit is greatly affected by race, gender, age, muscle mass, hydration and protein intake [10]. Blood urea nitrogen, anotherbiomarker incorporated into clinical practice several decades ago, is now considered as suboptimal for AKI as well. There is asystematic review by Huang and Don-Wauchope on the clinical utility of kidney injury molecule 1(Kim-1), a membraneprotein on proximal tubule epithelium, in the prediction, diagnosis and prognosis of AKI [11]. They analyze eight clinicalstudies and conclude that Kim-1 is a potential urinary biomarker in the early detection of AKI within 24 hours after kidneyinsult.Neutrophil gelatinase-associated lipocalin (NGAL) is another potential early biomarker for AKI. Its application is just beingstarted in clinical practice and there is a new urine NGAL assay available on automated ARCHITECT® immunoassay analyzer[12]. The clinical utilization of NGAL in AKI has already been reviewed in many excellent articles [13, 14]. Giasson et al.systematically review the clinical utilities of NGAL in body fluids (blood, urine, etc.) as a new biomarker for non-AKI diseasessuch as chronic kidney diseases (including lupus nephritis, glomerulonephritis, obstruction, renal dysplasia, polycystic kidneydisease, and IgA nephropathy), vascular disorders (including ANCA-associated vaculitis, Kawasaki disease, coronary artery disease and stroke), cancer, preeclampsia, infection, allergy, etc. [15]. It seems that NGAL may be a promising biomarker fornumerous non-AKI diseases, as well as for AKI.In conclusion, these inflammatory biomarkers discussed in this theme topic issue are shredding lights for the diagnosis,prediction, prevention, prognosis and monitoring of many diseases. With better understating of their roles in thepathophysiological mechanism of disease, potential therapeutic targets may also be developed. However, most of thesebiomarkers are pre-clinical or only at the early stage of clinical usage. More multi-center controlled prospective studies withrigorous study design and enough participants using standardized and validated analytical methods are needed to furtherevaluate their clinical utilities in diagnosis and therapy.

Pentraxins: CRP and PTX3 and Cardiovascular Disease by Yuichiro Maekawa, Toshiyuki Nagai, Atsushi Anzai (229-235).
The pentraxins, C-reactive protein (CRP), serum amyloid P (SAP) and pentraxin3 (PTX3) are usefulbiomarkers for cardiovascular disease (CVD), particularly ischemic heart disease and heart failure, and are deeplyinvolved in the pathogenesis of CVD linked to inflammation and innate immunity. Circulating elevated pentraxins,especially CRP and PTX3 levels can provide prognostic information for a variety of clinical settings and facilitate thediagnosis of CVD. Changes in these levels over time are also important indicators of pharmacological therapy, and mayindicate the mechanisms by which pentraxins directly or indirectly affect the pathophysiology of CVD in an experimentalsetting. Here, we discuss major relevant findings associated with the clinical implications of CRP and PTX3 and their rolein CVD.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been studied extensively in terms of biology,pathophysiology, diagnostic and prognostic values. Lp-PLA2 is an enzyme produced in atherosclerotic plaque byinflammatory cells, linked to LDL, HDL and VLDL. The binding of Lp-PLA2 to a specific lipoprotein fraction renders itmore atherogenic. Increasing evidence has demonstrated Lp-PLA2 as a novel “ideal” marker for CVD as of its highspecificity for vascular inflammation and low biologic variability. Thus, determination of Lp-PLA2 in individuals mayprovide clinically relevant information about their future risk of CVD events. In addition, Lp-PLA2 has been considered as atherapeutic target, which has been acted upon indirectly (lipid lowering medications) and directly (Lp-PLA2 antagonists suchas darapladib) in pharmacologic therapies. This review will provide an overview on biochemistry, biology, proatherogenic,proinflammatory and proapoptotic effects of Lp-PLA2. Clinical utility and its validity as an independent CVD biomarker aswell as a diagnostic biomarker to be detected in the very early stages of atherosclerosis will be also discussed. Moreover, therole of Lp-PLA2 as a pharmacologic therapeutic target is another theme of this review.

Heat Shock Proteins Protect Against Ischemia and Inflammation Through Multiple Mechanisms by Quinton Jones, Tracy S. Voegeli, Gefeng Li, Yu Chen, R. William Currie (247-259).
After heat shock or other metabolic stress, heat shock proteins (Hsps) are expressed at high levels in all tissues andcells. The highly inducible 70 kDa heat shock protein (Hsp70) is associated with improved post-ischemic myocardialcontractile recovery. Similarly, the small 27 kDa heat shock protein (Hsp27), that is abundant in muscle, is also linked withimproved myocardial function after ischemic injury. Various Hsps have pro-survival functions that include chaperone, antiapoptoticand/or anti-inflammatory activity. In this review we will summarize our understanding of myocardial protectionand present evidence for protection having time dependent aspects that appear to be stimulus dependent.

Objective: This systematic review evaluates the clinical utility of a novel biomarker kidney injury molecule 1(Kim-1) in the prediction, diagnosis and prognosis of acute kidney injury (AKI).Methods: We searched literature in electronic databases from January 2002 to December 2009 by the key words “kidneyinjury molecule 1” or “Kim-1” and “acute kidney injury” or “acute renal failure”. Studies were eligible for inclusion ifthey were primary studies published in English, in which Kim-1 was measured for the purpose of prediction, diagnosis orprognosis of AKI in patients.Results: Eight articles met the selection criteria for inclusion in the study. Compared to non AKI patients, Kim-1 increasedsignificantly (at least p<0.05) in AKI patients by 2 hours after cardiac surgery. In the prediction of AKI in patients within24 hours of cardiac surgery, the sensitivity of Kim-1 ranged from 92% to 100% and AUC between 0.78 and 0.91. Kim-1increased significantly (at least p<0.05) in AKI established patients, especially in patients with acute tubular necrosis(ATN). The AUC of Kim-1 in the diagnosis of AKI was from 0.9 to 0.95. However, Kim-1 showed weak association withthe need of renal replacement therapy and death of AKI patient.Conclusions: Kim-1 is a potential novel urinary biomarker in the early detection of AKI within 24 hours after kidneyinsult. It might be especially beneficial in the diagnosis of ischemic ATN.

Neutrophil gelatinase-associated lipocalin, or NGAL, an acute phase protein, is part of the lipocalin family.NGAL is highly induced in inflammatory conditions and ischemia, and is a critical component of innate immunity tobacterial infection. Recently, NGAL has been proven as an emerging biomarker for predicting acute kidney injury (AKI).Meanwhile, numerous studies have also demonstrated that NGAL may be a potential biomarker for the diagnosis,prediction, prevention, and prognosis of non-AKI diseases such as chronic kidney diseases, vascular disorders, cancer,preeclampsia, and allergies. This article systematically reviews the clinical utilities of NGAL as a new biomarker for non- AKI diseases.

Inflammation and Immunology of the Vitreoretinal Compartment by Michael R.R. Boehm, Patrick Oellers, Solon Thanos (283-309).
The immune system protects organisms against environmental and endogenous pathogens. By complexmechanisms, it regulates the homeostasis of inflammatory processes and tissue repair mechanisms. In the retina, thesepathways can result in an irreversible tissue scar, which is related to malfunction and loss of function. In the aging retina,inflammation plays a major role and causes adverse effects. Several ophthalmological diseases contain aspects ofmaladjusted inflammatory processes.This review summarizes the general function of the immune system and its regulatory mechanisms in the vitreoretinalcompartment. Next to non-pathological inflammatory processes, the review presents aspects of inflammation in the agingretina, AMD, glaucoma, uveitis and diabetic retinopathy. A better understanding of the complex immunology of the eyeand inflammation of the vitreoretinal compartment may guide us towards more effective therapies for these very prevalenteye conditions.

Erratum by Bentham Science Publishers (310-310).
Due to oversight an incorrect figure was published on page 315 in the article entitled “SclerodermaRenal Crisis Accompanied by New-Onset Pulmonary Hypertension: An Acute Systemic EndothelialInjury? Case Report and Literature Review”, Inflammation & Allergy - Drug Targets, 2010, Vol. 9,Issue no. 4, pp. 313-318. The correct figure is given below.....