Inhibition of cyclooxygenase-2 ameliorates the severity of pancreatitis and associated lung injury

2002 ◽  
Vol 283 (5) ◽  
pp. G1166-G1174 ◽  
Author(s):  
Albert M. Song ◽  
Lakshmi Bhagat ◽  
Vijay P. Singh ◽  
Gijs G. D. Van Acker ◽  
Michael L. Steer ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Lung Injury ◽  
Lavage Fluid ◽  
Cyclooxygenase 2 ◽  
Neutrophil Sequestration ◽  
Acinar Cell Necrosis ◽  
Cox 2 ◽  
Proinflammatory Role ◽  
Cox 2 Inhibitors

Cyclooxygenase-2 (COX-2), a widely distributed enzyme, plays an important role in inflammation. We have studied the role of COX-2 in acute pancreatitis and pancreatitis-associated lung injury using both the pharmacological inhibition of COX-2 and genetic deletion of COX-2. Pancreatitis was induced in mice by 12 hourly injections of cerulein. The severity of pancreatitis was assessed by measuring serum amylase, pancreatic trypsin activity, intrapancreatic sequestration of neutrophils, and acinar cell necrosis. The severity of lung injury was evaluated by measuring lactate dehydrogenase levels in the bronchoalveolar lavage fluid and by quantitating neutrophil sequestration in the lung. In both the pharmacologically inhibited and genetically altered mice, the severity of pancreatitis and pancreatitis-associated lung injury was reduced compared with the noninhibited strains of COX-2-sufficient mice. This reduction in injury indicates that COX-2 plays an important proinflammatory role in pancreatitis and its associated lung injury. Our findings support the concept that COX-2 inhibitors may play a beneficial role in the prevention of acute pancreatitis or in the reduction of its severity.

scholarly journals Cyclooxygenase-2 Activity Regulates Recruitment of VEGF-Secreting Ly6Chigh Monocytes in Ventilator-Induced Lung Injury

2019 ◽  
Vol 20 (7) ◽  
pp. 1771
Author(s):  
Tzu-Hsiung Huang ◽  
Pin-Hui Fang ◽  
Jhy-Ming Li ◽  
Huan-Yuan Ling ◽  
Chieh-Mo Lin ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Cyclooxygenase 2 ◽  
Leukocyte Infiltration ◽  
Pulmonary Vascular Permeability ◽  
Ventilator Induced Lung Injury ◽  
Cox 2

Mechanical ventilation is usually required for saving lives in critically ill patients; however, it can cause ventilator-induced lung injury (VILI). As VEGF-secreting Ly6Chigh monocytes are involved in VILI pathogenesis, we investigated whether cyclooxygenase-2 (COX-2) activity regulates the recruitment of VEGF-secreting Ly6Chigh monocytes during VILI. The clinically relevant two-hit mouse model of VILI, which involves the intravenous injection of lipopolysaccharide prior to high tidal volume (HTV)-mechanical ventilation, was used in this study. To investigate the role of COX-2 in the recruitment of VEGF-secreting Ly6Chigh monocytes during VILI, celecoxib, which is a clinical COX-2 inhibitor, was administered 1 h prior to HTV-mechanical ventilation. Pulmonary vascular permeability and leakage, inflammatory leukocyte infiltration, and lung oxygenation levels were measured to assess the severity of VILI. HTV-mechanical ventilation significantly increased the recruitment of COX-2-expressing Ly6Chigh, but not Ly6Clow, monocytes. Celecoxib significantly diminished the recruitment of Ly6Chigh monocytes, attenuated the levels of VEGF and total protein in bronchoalveolar lavage fluid, and restored pulmonary oxygenation during VILI. Our findings demonstrate that COX-2 activity is important in the recruitment of VEGF-secreting Ly6Chigh monocytes, which are involved in VILI pathogenesis, and indicate that the suppression of COX-2 activity might be a useful strategy in mitigating VILI.

Complement factor C5a exerts an anti-inflammatory effect in acute pancreatitis and associated lung injury

2001 ◽  
Vol 280 (5) ◽  
pp. G974-G978 ◽  
Author(s):  
Madhav Bhatia ◽  
Ashok K. Saluja ◽  
Vijay P. Singh ◽  
Jean-Louis Frossard ◽  
Hong-Sik Lee ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Lung Injury ◽  
Acute Inflammation ◽  
Complement Factor ◽  
Neutrophil Sequestration ◽  
C5a Receptors ◽  
Acinar Cell Necrosis ◽  
Anti Inflammatory ◽  
Type Strains ◽  
Inflammatory Effect

Complement factor C5a acting via C5a receptors (C5aR) is recognized as an anaphylotoxin and chemoattractant that exerts proinflammatory effects in many pathological states. The effects of C5a and C5aR in acute pancreatitis and in pancreatitis-associated lung injury were evaluated using genetically altered mice that either lack C5aR or do not express C5. Pancreatitis was induced by administration of 12 hourly injections of cerulein (50 μg/kg ip). The severity of pancreatitis was determined by measuring serum amylase, neutrophil sequestration in the pancreas, and acinar cell necrosis. The severity of lung injury was evaluated by measuring neutrophil sequestration in the lung and pulmonary microvascular permeability. In both strains of genetically altered mice, the severity of pancreatitis and pancreatitis-associated lung injury was greater than that noted in the comparison wild-type strains of C5aR- and C5-sufficient animals. This exacerbation of injury in the absence of C5a function indicates that, in pancreatitis, C5a exerts an anti-inflammatory effect. Potentially, C5a and its receptor are capable of both promoting and reducing the extent of acute inflammation.

Cyclooxygenase-2 (COX-2) gene disruption markedly attenuates the severity of acute pancreatitis and pancreatitis-associated lung injury

2000 ◽  
Vol 118 (4) ◽  
pp. A166 ◽  
Author(s):  
Richard T. Ethridge ◽  
Dai H. Chung ◽  
Richard A. Ehlers ◽  
Srinivasan Rajaraman ◽  
B. Mark Evers
Keyword(s):  
Acute Pancreatitis ◽  
Lung Injury ◽  
Gene Disruption ◽  
Cyclooxygenase 2 ◽  
Cox 2

Cyclooxygenase-2: a target for the prevention and treatment of breast cancer.

2001 ◽  
pp. 97-114 ◽  
Author(s):  
L R Howe ◽  
K Subbaramaiah ◽  
A M Brown ◽  
A J Dannenberg
Keyword(s):  
Breast Cancer ◽  
Mammary Tumorigenesis ◽  
Cyclooxygenase 2 ◽  
Cancer Data ◽  
Prostaglandin Synthase ◽  
Tumour Formation ◽  
Prevention And Treatment ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Cyclooxygenase-2 (COX-2), an inducible prostaglandin synthase, is normally expressed in parts of the kidney and brain. Aberrant COX-2 expression was first reported in colorectal carcinomas and adenomas, and has now been detected in various human cancers, including those of the breast. Strikingly, COX-2 overexpression in murine mammary gland is sufficient to cause tumour formation. To date, the role of COX-2 in tumorigenesis has been most intensively studied in the colon. Thus, the relationship between COX-2 and neoplasia can best be illustrated with reference to intestinal tumorigenesis. Here we consider the potential utility of selective COX-2 inhibitors for the prevention and treatment of breast cancer. Data for cancers of the colon and breast are compared where possible. In addition, the mechanisms by which COX-2 is upregulated in cancers and contributes to tumorigenesis are discussed. Importantly, several recent studies of mammary tumorigenesis in animal models have found selective COX-2 inhibitors to be effective in the prevention and treatment of breast cancer. Clinical trials will be needed to determine whether COX-2 inhibition represents a useful approach to preventing or treating human breast cancer.

RELATIVE ROLE OF CYCLOOXYGENASE-2 (COX-2) INHIBITORS AND LIPOXYGENASE (LOX) INHIBITORS IN AGING INDUCED DEMENTIA AND OXIDATIVE DAMAGE

2005 ◽  
Vol 12 (02) ◽  
pp. 6-11 ◽  
Author(s):  
Mahendra Bishnoi ◽  
Chandrashekhar S Patii ◽  
Anil Kumar ◽  
Shrinivas K Kulkarni
Keyword(s):  
Oxidative Damage ◽  
Cyclooxygenase 2 ◽  
Relative Role ◽  
Cox 2 ◽  
Lox Inhibitors ◽  
Cox 2 Inhibitors

scholarly journals Cyclooxygenase-2 (COX-2) inhibitors: future therapeutic strategies for epilepsy management

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Chitra Rawat ◽  
Samiksha Kukal ◽  
Ujjwal Ranjan Dahiya ◽  
Ritushree Kukreti
Keyword(s):  
Underlying Mechanism ◽  
Cyclooxygenase 2 ◽  
World Population ◽  
Clinical Settings ◽  
Dose Time ◽  
Proinflammatory Mediators ◽  
Pathophysiological Role ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Abstract Epilepsy, a common multifactorial neurological disease, affects about 69 million people worldwide constituting nearly 1% of the world population. Despite decades of extensive research on understanding its underlying mechanism and developing the pharmacological treatment, very little is known about the biological alterations leading to epileptogenesis. Due to this gap, the currently available antiepileptic drug therapy is symptomatic in nature and is ineffective in 30% of the cases. Mounting evidences revealed the pathophysiological role of neuroinflammation in epilepsy which has shifted the focus of epilepsy researchers towards the development of neuroinflammation-targeted therapeutics for epilepsy management. Markedly increased expression of key inflammatory mediators in the brain and blood-brain barrier may affect neuronal function and excitability and thus may increase seizure susceptibility in preclinical and clinical settings. Cyclooxygenase-2 (COX-2), an enzyme synthesizing the proinflammatory mediators, prostaglandins, has widely been reported to be induced during seizures and is considered to be a potential neurotherapeutic target for epilepsy management. However, the efficacy of such therapy involving COX-2 inhibition depends on various factors viz., therapeutic dose, time of administration, treatment duration, and selectivity of COX-2 inhibitors. This article reviews the preclinical and clinical evidences supporting the role of COX-2 in seizure-associated neuroinflammation in epilepsy and the potential clinical use of COX-2 inhibitors as a future strategy for epilepsy treatment.

scholarly journals Protective Effect of Quercetin, a Flavonol against Benzo(a)pyrene-Induced Lung Injury via Inflammation, Oxidative Stress, Angiogenesis and Cyclooxygenase-2 Signalling Molecule

2021 ◽  
Vol 11 (18) ◽  
pp. 8675
Author(s):  
Mohammad A. Alzohairy ◽  
Amjad Ali Khan ◽  
Mohammad Azam Ansari ◽  
Ali Yousif Babiker ◽  
Mohammed A. Alsahli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Treatment Group ◽  
Lung Injury ◽  
Inflammatory Cytokines ◽  
Cyclooxygenase 2 ◽  
Inflammatory Factors ◽  
Control Group ◽  
Cox 2

Quercetin (Qu) is an important polyphenolic flavonoid which exhibits tremendous antioxidant, anti-inflammatory and other health promoting effects. The aim of the current study was to explore the therapeutic role of Qu on benzo(a)pyrene [B(a)P]-induced lung injury in rats. B(a)P was given to the rats at dose of 50 mg/kg b.w. for continues 8 weeks through oral gavage. The rats were treated with Qu at dose of 50 mg/kg b.w prior 30 min before the oral administration of B(a)P. The effects of Qu were studied by measuring the level of lactate dehydrogenase (LDH), anti-oxidant enzymes, lipid peroxidation, inflammatory cytokines, lung tissues architecture and expression of cyclooxygenase-2 (COX-2). The level of pro‑inflammatory cytokines such as IL-1β (27.30 vs. 22.80 pg/mL), IL-6 (90.64 vs. 55.49 pg/mL) and TNF-α (56.64 vs. 40.49 pg/mL) increased significantly and antioxidant enzymes decreased significantly in benzopyrene-induced lung injury in comparison to the control group. The treatment with Qu potentially reversed the effects of B(a)P to a great extent, as it led to the enhancement of antioxidant enzymes and decreased proinflammatory cytokines level. A significant surge of VEGF level was noticed in the B(a)P group as compared to the control group, while the Qu treatment groups exhibited less angiogenesis as lower level of VEGF levels, compared with the B(a)P treatment group. The Qu treatment significantly decreased the degrees of histopathological changes and collagen deposition in B(a)P-induced lung injury. The B(a)P-treated group showed higher cytoplasmic expression of COX-2 protein, which significantly decreased in the Qu treatment group. These outcomes recommend an effective role of Qu in the protection of lung injury against B(a)P through the regulation of the inflammatory factors, oxidative stress and the maintenance lung tissue architecture.

scholarly journals Chronic Low-Level Lead Exposure Increases Mesenteric Vascular Reactivity: Role of Cyclooxygenase-2-Derived Prostanoids

2021 ◽  
Vol 11 ◽  
Author(s):  
Maylla Ronacher Simões ◽  
Bruna Fernandes Azevedo ◽  
María Jesús Alonso ◽  
Mercedes Salaices ◽  
Dalton Valentim Vassallo
Keyword(s):  
Lead Exposure ◽  
Vascular Reactivity ◽  
Cyclooxygenase 2 ◽  
Resistance Arteries ◽  
Induced Hypertension ◽  
Pb Exposure ◽  
Cox 2 ◽  
Underlying Mechanisms ◽  
Cox 2 Inhibitors

Lead (Pb) exposure causes hazardous effects as hypertension and other cardiovascular diseases. We evaluated whether chronic Pb exposure alters the peripheral vascular resistance measuring the vascular reactivity of mesenteric resistance arteries in rats to identify the underlying mechanisms that are associated to the development of Pb-induced hypertension. Mesenteric resistance arteries from lead-treated and untreated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) were used. Contractile responses to phenylephrine increased, while acetylcholine and sodium nitroprusside-induced relaxation was not affected by lead treatment. Endothelium removal and inhibition of NO synthase by L-NAME similarly enhanced the response to phenylephrine in untreated and lead-treated rats. The antioxidants apocynin and superoxide dismutase (SOD) did not affect vasoconstriction in either group. The vascular expression of cyclooxygenase-2 (COX-2) protein increased after lead exposure. The respective non-specific or specific COX-2 inhibitors indomethacin and NS398 reduced more strongly the response to phenylephrine in treated rats. Antagonists of EP1 (SC19220), TP (SQ29548), IP (CAY10441) and angiotensin II type 1 (losartan) receptors reduced vasoconstriction only in treated rats. These conclusions present further evidence that lead, even in small concentration, produces cardiovascular hazards being an environmental contaminant that account for lead-induced hypertension.

scholarly journals TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia

2012 ◽  
Vol 302 (5) ◽  
pp. L447-L454 ◽  
Author(s):  
Louis R. Standiford ◽  
Theodore J. Standiford ◽  
Michael J. Newstead ◽  
Xianying Zeng ◽  
Megan N. Ballinger ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bacterial Pneumonia ◽  
Lavage Fluid ◽  
Alveolar Epithelial Cells ◽  
Intratracheal Administration ◽  
Bacterial Colony ◽  
Gram Negative ◽  
Gm Csf

Toll-like receptors (TLRs) are required for protective host defense against bacterial pathogens. However, the role of TLRs in regulating lung injury during Gram-negative bacterial pneumonia has not been thoroughly investigated. In this study, experiments were performed to evaluate the role of TLR4 in pulmonary responses against Klebsiella pneumoniae (Kp). Compared with wild-type (WT) (Balb/c) mice, mice with defective TLR4 signaling (TLR4lps-d mice) had substantially higher lung bacterial colony-forming units after intratracheal challenge with Kp, which was associated with considerably greater lung permeability and lung cell death. Reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA and protein was noted in lungs and bronchoalveolar lavage fluid of TLR4 mutant mice postintratracheal Kp compared with WT mice, and primary alveolar epithelial cells (AEC) harvested from TLR4lps-d mice produced significantly less GM-CSF in vitro in response to heat-killed Kp compared with WT AEC. TLR4lps-d AEC underwent significantly more apoptosis in response to heat-killed Kp in vitro, and treatment with GM-CSF protected these cells from apoptosis in response to Kp. Finally, intratracheal administration of GM-CSF in TLR4lps-d mice significantly decreased albumin leak, lung cell apoptosis, and bacteremia in Kp-infected mice. Based on these observations, we conclude that TLR4 plays a protective role on lung epithelium during Gram-negative bacterial pneumonia, an effect that is partially mediated by GM-CSF.

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