Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer.

Diseases related to chronic persisting inflammation are amongst the largest sources of morbidity and health costs, yet biomarkers for early diagnosis, prognosis, and treatment response are not sufficiently effective.
This narrative review discusses how inflammation concepts have evolved from ancient times to the present, and places in perspective the use of blood-based biomarkers to assess chronic inflammatory diseases. From reviews of biomarkers in specific diseases, emerging biomarker classifiers and their clinical utility is discussed. Biomarkers representative of systemic inflammatory response such as C Reactive Protein are distinguished from local tissue inflammation markers such as cell membrane components and molecules involved in matrix degradation. The application of newer methodologies such as gene signatures, non-coding RNA, and artificial intelligence/machine-learning techniques is highlighted.
The dearth of novel biomarkers for chronic inflammatory diseases can be ascribed in part to the lack of basic understanding about non-resolving inflammation, and in part by fragmentation of effort whereby individual diseases are studied but their pathophysiologic commonalities and differences are neglected. Finding better blood biomarkers for chronic inflammatory diseases may be best addressed by studying cell and tissue products of local inflammation, augmenting data interpretation by artificial intelligence techniques.

Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (i.e., \"eat-me\" signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft-versus-host disease) inflammatory diseases.

Arachidonate 5-lipoxygenase (ALOX5)-derived leukotrienes are primary signals of leukocyte activation and inflammation in response to ischemic cardiac injury (MI; myocardial infarction). Using risk-free male C57BL/6J and ALOX5-null mice (8-12 wk), we quantitated leukocytes and ALOX5-derived bioactive lipids of the infarcted left ventricle (LV) and spleen to measure the physiological inflammation and cardiac repair. Our results showed that ALOX5 endogenously generates specialized pro-resolving mediators (SPMs) that facilitate cardiac repair post-MI. Deficiency of ALOX5 leads to increase in cyclooxygenase gene expression, 6-keto prostaglandin F1α, and delayed neutrophil clearance with signs of unresolved inflammation post-MI. Consequently, ALOX5 deficiency impaired the resolution of inflammation and cardiac repair, including increased myocardium rupture post-MI in acute heart failure. On-time ALOX5 activation is critical for leukocyte clearance from the infarcted heart, indicating an essential role of ALOX5 in the resolution of inflammation. In addition, to balance the inflammatory responses, ALOX5 is also necessary for fibroblast signaling, as the ALOX5-deficient fibroblast are prone to fibroblast-to-myofibroblast differentiation leading to defective scar formation in post-MI cardiac repair. Consistent with these findings, ALOX5-null mice showed an overly inflammatory response, defective fibrotic signaling, and unresolved inflammation. These findings are indicative of a critical role of ALOX5 in myocardium healing, inflammation-resolution signaling, cardiac repair, and fibroblast pathophysiology.NEW & NOTEWORTHY Arachidonate 5-lipoxygenase (ALOX5) is critical in synthesizing specialized pro-resolving mediators that facilitate cardiac repair after cardiac injury. Thus, ALOX5 orchestrates the overlapping phases of inflammation and resolution to facilitate myocardium healing in cardiac repair postmyocardial infarction.

Unresolved inflammation is a key mediator of advanced heart failure. Especially, damage, pathogen, and lifestyle-associated molecular patterns are the major factors in initiating baseline inflammatory diseases, particularly in cardiac pathology. After a significant cardiac injury like a heart attack, splenic and circulating leukocytes begin a highly optimized sequence of immune cell recruitment (neutrophils and monocytes) to coordinate effective tissue repair. An injured cardiac tissue repair and homeostasis are dependent on clearance of cellular debris where the recruited leukocytes transition from a pro-inflammatory to a reparative program through resolution process. After a cardiac injury, macrophages play a decisive role in cardiac repair through the biosynthesis of endogenous lipid mediators that ensure a timely tissue repair while avoiding chronic inflammation and impaired cardiac repair. However, dysregulation of resolution of inflammation processes due to cardiometabolic defects (obesity, hypertension, and diabetes), aging, or co-medication(s) lead to impaired cardiac repair. Hence, the presented review demonstrates the fundamental role of leukocytes, in particular macrophages orchestrate the inflammation and resolution biology, focusing on the biosynthesis of specialized lipid mediators in cardiac repair and heart failure. This work was supported by research funds from National Institutes of Health (AT006704, HL132989, and HL144788) to G.V.H. The authors acknowledges the use of Servier Medical Art image bank and Biorender that is used to create schematic Figures 1-3.

Heart failure with preserved ejection fraction (HFpEF) has been an emerging type of cardiac disease since the pseudo-left ventricle function is preserved; therefore, challenges in finding the target and treatment. Damage and pathogen-associated molecular patterns (DAMPs and PAMPs) are widely investigated in acute and chronic inflammation in heart failure; however, lifestyle-associated molecular patterns (LAMPs: diet, sleep, exercise), particularly in obesity, remains of interest due to the enormous increase of HFpEF patients. In this review, we covered obesity-related cardiomyopathy, LAMPs, and resolution receptor dysfunction in the context of heart failure with preserved ejection fraction.

Chronic unresolved inflammation is the primary determinant of cardiovascular disease. Precise mechanisms that define the genesis of unresolved inflammation in heart failure with preserved ejection fraction (HFpEF) are of interest due to the obesity epidemic. To examine the obesity phenotype and its direct/indirect consequences, multiple approaches were employed using the lipoxin receptor (abbreviated as ALX) dysfunction mouse model. Indirect calorimetry analyses revealed that the deletion of ALX dysregulated energy metabolism driving toward age-related obesity. Heart function data suggest that obesity-prone ALX deficient mice had impaired myocardium strain. Comprehensive measurement of chemokines, extracellular matrix, and arrhythmogenic arrays confirmed the dysregulation of multiple ion channels gene expression with amplified inflammatory chemokines and cytokines response at the age of 4 months compared with WT counterparts. Quantitative analyses of leukocytes demonstrated an increase of proinflammatory Ly6Chi CCR2+ macrophages in the spleen and heart at a steady-state resulting in an inflamed splenocardiac axis. Signs of subtle inflammation were marked with cardiorenal, endothelial defects with decreased CD31 and eNOS and an increased iNOS and COX2 expression. Thus, ALX receptor deficiency serves as an experimental model that defines multiple cellular and molecular mechanisms in HFpEF that could be a target for the development of HFpEF therapy in cardiovascular medicine.

Amplified innate leukocytes (neutrophils and monocytes/macrophages) are associated with advanced ischemic and non-ischemic heart failure (HF). Intensified neutrophilic leukocytosis (neutrophilia) and sustained activation of neutrophils is the predominant factor that determines over activated inflammation in acute HF and the outcome of long-term chronic HF. After heart attack, the first wave of innate responsive and short-lived neutrophils is essential for the initiation of inflammation, resolution of inflammation, and cardiac repair, however uncontrolled and long-term activation of neutrophils leads to collateral damage of myocardium. In the presented review, we highlighted the interactive and integrative role of neutrophil phenotypes in cellular and molecular events of ischemic HF. In addition, we discussed the current, nonimmune, immune, and novel paradigms of neutrophils in HF associated with differential factors with a specific interest in non-resolving inflammation and resolution physiology.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are commonly used to control pain, inflammation, and limit the cardinal signs of injury in humans. However, prolonged use of NSAIDs increases the risk of heart attack (myocardial infarction; MI) and the subsequent risk of heart and renal failure. The molecular and cellular mechanism of action for this adverse effect, particularly along the cardiorenal network, is incomplete. To define the mechanism, carprofen (CAP), an NSAID was administered at the dose of 5 mg/kg to C57BL/6 male mice for two weeks. After last dose of CAP treatment mice were subjected to permanent occlusion of coronary artery that induces irreversible cardiac remodeling while maintaining naive and MI-controls. After MI, cardiac pathology and dysfunction were confirmed, along with additional measurements of kidney function, histology, and injury markers, such as plasma creatinine. CAP treatment increased plasma creatinine levels and subsequently, myocardial structural disorganization increased. Kidney neutrophil gelatinase associated lipocalin (NGAL) and protein expression were increased post-MI. After two weeks CAP treatment, the expression of pyrogenic pro-inflammatory cytokines TNF-α and IL-1β was increased compared to non-CAP treated mice, indicative of amplified inflammatory response. There was also evidence that renal injury of both the post-CAP treatment controls and post-CAP MI were much greater than the non-CAP treated naïve controls, as serum creatinine and NGAL levels were elevated along with obvious structural impairment of the glomerulus. Therefore, CAP treatment tampers with the acute inflammatory response that promotes cardiorenal syndrome and non-resolving inflammation post-MI in acute heart failure.

Post-myocardial infarction (MI), overactive inflammation is the hallmark of aging, however, the mechanism is unclear. We hypothesized that excess influx of omega 6 fatty acids may impair resolution, thus impacting the cardiosplenic and cardiorenal network post-MI. Young and aging mice were fed on standard lab chow (LC) and excess fatty acid (safflower oil; SO)-enriched diet for 2 months and were then subjected to MI surgery. Despite similar infarct areas and left ventricle (LV) dysfunction post-MI, splenic mass spectrometry data revealed higher levels of arachidonic acid (AA) derived pro-inflammatory metabolites in young-SO, but minimal formation of docosanoids, D- and E- series resolvins in SO-fed aged mice. The aged mice receiving excess intake of fatty acids exhibit; 1) decreased lipoxygenases (5-,12-, and 15) in the infarcted LV; 2) lower levels of 14HDHA, RvD1, RvD5, protectin D1, 7(S)maresin1, 8-,11-,18-HEPE and RvE3 with high levels of tetranor-12-HETEs; 3) dual population of macrophages (CD11blow/F480high and CD11bhigh/F480high) with increased pro-inflammatory (CD11bp+F4/80+Ly6Chi) phenotype and; 4) increased kidney injury marker NGAL with increased expression of TNF-α and IL-1β indicating MI-induced non-resolving response compared with LC-group. Thus, excess fatty acid intake magnifies the post-MI chemokine signaling and inflames the cardiosplenic and cardiorenal network towards a non-resolving microenvironment in aging.