Chediak-Higashi Syndrome With Epstein-Barr Virus Triggered Hemophagocytic Lymphohistiocytosis: A Case Report.

Chediak-Higashi syndrome (CHS) is a rare, autosomal-recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections, progressive neurologic abnormalities, coagulation defects and a high risk of developing hemophagocytic lymphohistiocytosis characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult with poor prognosis. Here, we report a two-and-a-half-year-old male child who was diagnosed with Chediak-Higashi Syndrome based on silvery hair, pathognomonic hair microscopy and giant azurophilic granules in granulocytes. The patient was in advanced stage of HLH induced by an Epstein-Barr virus (EBV) infection and given etoposide, cyclosporine and dexamethasone according to hemophagocytic lymphohistiocytosis (HLH)-2004 protocol but did not survive.

Basic and clinical aspects of bradykinin receptor antagonists.

Bradykinin and related kinins may act on two types of receptors designated as B1 and B2. It seems that the B2 receptors are most commonly found in various vascular and non-vascular smooth muscles, whereas B1 receptors are formed in vitro during trauma, and injury, and are found in bone tissues. These bradykinin (BK) receptors are involved in the regulation of various physiological and pathological processes. The mode of kinin actions are based upon the interactions between the kinin and their specific receptors, which can lead to activation of several second-messenger systems. Recently, numerous BK receptor antagonists have been synthesized with prime aim to treat diseases caused by excessive kinin production. These diseases are rheumatoid arthritis (RA), inflammatory diseases of the bowel, asthma, rhinitis and sore throat, allergic reactions, pain, inflammatory skin disorders, endotoxic and anaphylactic shock and coronary heart diseases. On the other hand, BK receptor antagonists could be contraindicated in hypertension, since these drugs may antagonize the antihypertensive therapy and/ or may trigger the hypertensive crisis. It is worth suggesting that the BK receptor agonists might be useful antihypertensive drugs.

The kallikrein-kinin pathways in hypertension and diabetes.

Cardiovascular diseases are the most common causes of mortality worldwide. Hypertension and diabetes are the two major risk factors in the development of cardiac hypertrophy, ischemic heart disease, and cardiac failure. In Kuwait, high rate of prevalence of hypertension and diabetes has been documented. Previous studies have indicated altered activities of the BK-generating components in hypertension and diabetes. Bradykinin is pharmacologically active polypeptide that can promote both cardiovascular and renal function, for example, vasodilation, natriuresis, diuresis, and release of nitric oxide (NO). In addition, B2 kinin receptors are present in the cardiac endothelial cells which may enhance the biosynthesis and release of NO. It has been demonstrated that reduced urinary (renal) kallikrein levels may be associated with the development of high blood pressure in humans and spontaneously hypertensive and diabetic rats. The BK may produce its pharmacological effects via NO and cyclic GMP release. Furthermore, it is established that the BK has cardioprotective actions in myocardial ischemia and can prevent left ventricular hypertrophy. Also, transgenic mice carrying tissue kallikrein gene and overexpressing tissue kallikrein had reduced blood pressure. NO synthase and renal tissue kallikrein are both involved in blood pressure regulation. The ability of kallikrein gene delivery and the use of kinin B2 receptor agonists to produce a wide spectrum of beneficial effects make it a powerful candidate in treating hypertension, cardiovascular, and renal diseases. Strategies that activate kinin receptors might be applicable to the treatment of cardiovascular disease. Increased plasma prekallikrein levels in diabetic patients may serve as an indicator of developing hypertension and renal damage. Also high plasma and urine concentrations of tissue kallikrein may cause higher glucose levels in the blood.

The kinin system in hypertensive pathophysiology.

Cardiovascular diseases are the prime cause of death in the world. The kallikrein-kinin system has been implicated in the pathophysiology of the vascular smooth muscle and cardiac dysfunctions. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction and left ventricular hypertrophy, have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective actions of the angiotensin-converting enzyme inhibitors are primarily dependent on protecting the kinin-forming components, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.

Hypertension and the bradykinin system.

The blood pressure-lowering property of the brady-kinin system has been documented for more than eight decades. The bradykinin system is involved in the mediation and modulation of the vasoconstrictor renin-angiotensin system and the vasodilators prostaglandin, prostacyclin, and nitric oxide in regulating sodium water balance, renal and cardiac hemodynamics, and blood pressure. Reduced activity of the bradykinin system has been observed in various hypertensive situations in both clinical and experimental models of hypertension. Antihypertensive properties of the angiotensin-converting enzyme or kininase II inhibitors are primarily mediated via the bradykinin-releasing pathway, which may also cause regression of left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate for treating hypertension and cardiovascular and renal diseases. In addition, stable bradykinin agonists may also be available in the future as therapeutic agents for cardio-vascular and renal disorders.

Cardiovascular activities of the bradykinin system.

All the components of the kallikrein-kinin system are located in the cardiac muscle and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction, and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin-converting enzyme inhibitors is primarily mediated via a kinin-releasing pathway, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it a promising candidate in treating hypertension and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders. However, there are also possibilities of adverse effects that may be caused by these compounds.

Role of tissue kallikrein-kininogen-kinin pathways in the cardiovascular system.

All the components of the kallikrein-kinin system are located in the cardiac muscle, and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin converting enzyme inhibitors is primarily mediated via kinin-releasing pathway, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.

The kallikrein-kinin system: from mediator of inflammation to modulator of cardioprotection.

Kinin is an important mediator of hyperalgesia, inflammatory conditions and asthma. It causes pain, inflammation, increased vascular permeability and vasodilatation. Several kinin antagonists have been developed with the aim of treating these pathologies. Kinin B2 receptor agonists and kallikrein may have clinical utility in the treatment of hypertension, left ventricular hypertrophy, ischemic heart disease, congestive heart failure and diabetes. However, there is a need to know whether there is a safe therapeutic window between potential cardio-protective and pro-inflammatory effects following administration of kinin B2 receptor agonists.

Adverse effects of COX-2 inhibitors.

Cyclooxygenase-2 selective inhibitors (COXIBs) were developed with the prime object of minimizing gastrointestinal adverse effects, which are seen with the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Their long-term use is limited by the development of hypertension, edema, and congestive heart failure in a significant proportion of patients. NSAIDs block the activity of both COX isozymes, COX-1 and COX-2, which mediate the enzymatic conversion of arachidonate to prostaglandin H2 (PGH2) and other prostaglandin (PG) metabolites. It is well established that the cardiovascular profile of COX-2 inhibitors can be accounted for by inhibition of COX-dependent PG synthesis. Following the COX-mediated synthesis of PGH2 from arachidonate, PGH2 is metabolized to one of at least five bioactive PGs, including PGE2, PGI2, PGF2, PGD2, or thromboxane A2 (TXA2). These prostanoids have pleiotropic cardiovascular effects, altering platelet function and renal function, and they are acting either as vasodilators or vasoconstrictors. Although COX-1 and COX-2 exhibit similar biochemical activity in converting arachidonate to PGH2 in vitro, the ultimate prostanoids they produce in vivo may be different due to differential regulation of COX-1 and COX-2, tissue distribution, and availability of the prostanoid synthases. PGs have been established as being critically involved in mitigating hypertension, helping to maintain medullary blood flow (MBF), promoting urinary salt excretion, and preserving the normal homeostasis of thrombosis, and the researchers found that the use of COX-2 inhibitors caused many serious complications in altering the normal body homeostasis. The purpose of the present research is to explain briefly the side effects of COX-2 inhibitors on the renal and cardiovascular system.

A bradykinin antagonist abolishes beneficial effect of captopril on duration of survival after acute coronary artery ligation in hypertensive rats.

It has been recently suggested that bradykinin (BK) may act as a cardioprotective agent. In the present investigation, we evaluated the effects of captopril, an angiotensin-converting enzyme inhibitor (ACEI), and kinin B2 receptor antagonist, D-Arg-[Hyp3-D-Phe7]-BK, on the duration of survival after acute coronary artery ligation for 15 min in spontaneously hypertensive rats (SHR). The captopril treatment (16 and 32 ug/kg, i.v.) resulted in a significant (p < 0.05) increase in survival time of SHR as compared with saline-treated control SHR. Kinin B2 receptors antagonist (4 ug/kg, i.v.) pretreatment abolished (p > 0.05) the beneficial effect of captopril on survival time as compared to saline-treated control SHR. Both the ligation of coronary artery and captopril treatment resulted in a significant (p < 0.001) fall in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) of SHR as compared to the saline-treated control SHR. In addition, captopril administration caused a significant (p < 0.05) fall in the SBP, DBP and HR of SHR before ligation of the coronary artery (preligation). However, there was no significance (p > 0.05) in SBP, DBP and HR between saline- and kinin B2 receptor antagonist plus captopril-treated SHR during preligation. These finding might indicate that captopril possesses a cardioprotective property as demonstrated by increased in survival time of SHR. This beneficial effect of captopril is mediated via the kinin B2 receptor pathway because kinin B2 receptor antagonist pretreatment blocked the captopril-induced increase in survival time of SHR.

Therapeutic prospects for bradykinin receptor agonists in the treatment of cardiovascular diseases.

Kinins are located in the vascular smooth muscle and the heart, and are the most potent biologically active polypeptides. Pharmacological studies of cardiovascular disorders, including hypertension, cardiac failure, ischemia, myocardial infarction and left ventricular hypertrophy, indicate that reduced activity of the local kallikrein-kinin system (KKS) may be instrumental in the induction of these disorders. The ability of kallikrein gene delivery and bradykinin (BK) B2 receptor agonists to produce a wide spectrum of beneficial effects make them excellent candidate therapies for the treatment of hypertension, and cardiovascular and renal diseases. In addition, strategies that activate kinin receptors may be applicable to the treatment of cardiovascular and renal disorders. However, one major challenge of this approach is the unanswered question of whether there is a sufficiently safe therapeutic index between the potential cardioprotective and pro-inflammatory effects following administration of BK B2 receptor agonists.

Comparison between plethysmometer and micrometer methods to measure acute paw oedema for screening anti-inflammatory activity in mice.

The present study was undertaken to evaluate the sensitivity of the plethysmometer and micrometer, which are the most commonly employed methods to measure the paw oedema for screening anti-inflammatory agents. Acute paw swelling was induced by s.c. injection of 0.02 ml carrageenan in mice. The maximum paw oedema (59.4%) was found to be at 3.5 h after injection of carrageenan in the hind paw of mice. Oral indomethacin treatment in the dose of 5 mg/kg 1 h prior to the induction of paw oedema, caused a significant (P < 0.05) reduction in paw swelling, when the plethysmometer method was used. When the micrometer method was used to measure the paw swelling, oral indomethacin at the dose of 1 mg/kg resulted in a significant reduction in paw oedema. These findings suggest that micrometer method is more sensitive to detect the lowest antiinflammatory dose of indomethacin when compared with the plethysmometer method. The possible significance of these findings is discussed.

Tissue kallikrein increases duration of survival after prolonged coronary artery ligation in hypertensive rats.

There is evidence that the kallikrein-kinin system (KKS) is an important mediator in the regulation of blood pressure, and cardiac and renal hemodynamics. The present study was designed to examine the effect of tissue kallikrein and Trasylol, an inhibitor of tissue kallikrein, on survival time after continuous (prolonged) coronary artery ligation in spontaneously hypertensive rats (SHR). Tissue kallikrein (8 and 16 microg/kg, i.v.) treatment caused significant (p < 0.05) increases in the survival time of SHR as compared with the saline-treated control SHR. Trasylol pretreatment abolished (p < 0.05) the beneficial effect of tissue kallikrein on survival time. The tissue kallikrein treatment resulted in a significant (p < 0.05) reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) of SHR as compared to the saline-treated control SHR. Trasylol (6 microg/kg) treatment antagonized the effects of tissue kallikrein associated with survival time, SBP, DBP and HR. Ligation of the coronary artery caused a significant (p < 0.001) reduction in the SBP, DBP and HR of SHR, when the mean values were compared between before coronary artery ligation and after coronary artery ligation. However, there was no significant difference (p > 0.05) in SBP, DBP and HR between saline and kallikrein-treated SHR after coronary artery ligation. These findings may suggest that tissue kallikrein is able to act as a cardioprotective agent as demonstrated by an increase in survival time of SHR with prolonged coronary artery ligation.

Does the kinin system mediate in cardiovascular abnormalities? An overview.

All the components of the kallikrein-kinin system are located in the cardiac muscle, and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction, and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin-converting enzyme inhibitors is primarily mediated via the kinin-releasing pathway, which may cause regression of left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.

Bradykinin receptor antagonists: therapeutic implications.

Bradykinin (BK) is an important mediator of hyperalgesia, inflammatory diseases, asthma and cancer. It is a pro-inflammatory polypeptide that can cause pain, inflammation, increased vascular permeability, vasodilation, contraction of various smooth muscles and cell proliferation by stimulating B(1)and B(2)receptors. B(1) receptors are formed in vitro during trauma, inflammatory reactions and injury. B(2) receptors are most commonly distributed in the vascular and non-vascular smooth muscle, and in the heart. Numerous BK antagonists have been developed in recent years with the prime aim of treating diseases resulting from excessive BK formation. Non-peptide B(2) receptor antagonists are now being synthesized and are under intense experimental investigation at various research centers. The most clinically useful peptide and non-peptide BK antagonists must be stable against all BK-inactivating enzymes, orally active, and have a long half-life with minimal side effects. These BK receptor antagonists may have future novel therapeutic applications in various pathological conditions associated with the abnormal kinin system.

Evaluation of tissue kallikrein activity on survival time after acute coronary artery ligation in hypertensive rats.

It is known that the tissue kallikrein-kinin system is located in the cardiac tissue, and the lack of this system in the cardiac tissue might induce cardiac dysfunctions. In this study, we investigated the potential role of tissue kallikrein and Trasylol, an inhibitor of tissue kallikrein, on survival time with acute left coronary artery ligation for 15 min in spontaneously hypertensive rats (SHR). Tissue kallikrein (8 and 16 microg/kg, i.v.) treatment caused significant (P<0.05) increases in the survival time of SHR as compared with the saline-treated control SHR. Trasylol pretreatment abolished (P<0.05) the beneficial effect on tissue kallikrein on survival time. The ligation of coronary artery resulted in significant (P<0.05) reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) of SHR compared with the saline-treated control SHR. The tissue kallikrein treatment caused greater (P<0.001) reduction in the SBP, DBP and HR of SHR, when the mean values were compared between before coronary artery ligation and after coronary artery ligation. Trasylol (6 microg/kg) treatment antagonized the effects of tissue kallikrein associated with survival time, SBP, DBP and HR. These findings may suggest that tissue kallikrein is able to act as a cardioprotective agent as demonstrated by the increase in survival time of SHR with acute coronary artery ligation. The significance of these observations is discussed.

Cardiovascular properties of the kallikrein-kinin system.

All the components of the kallikrein-kinin system are located in the vascular smooth muscle as well as in the heart. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischaemia, myocardial infarction and left ventricular hypertrophy, have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental in the induction of cardiovascular-related diseases. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.

Effect of captopril on urinary kallikrein, blood pressure and myocardial hypertrophy in diabetic spontaneously hypertensive rats.

We investigated the total urinary kallikrein levels, left-ventricular wall thickness and mean arterial blood pressure of nontreated and captopril-treated diabetic and nondiabetic spontaneously hypertensive rats. The mean arterial blood pressure was significantly elevated in diabetic spontaneously hypertensive rats as compared to nondiabetic spontaneously hypertensive rats. Captopril treatment caused a significant reduction in the arterial blood pressure of both nondiabetic and diabetic spontaneously hypertensive rats. The left-ventricular wall thickness was also significantly reduced in diabetic and nondiabetic spontaneously hypertensive treated with captopril as compared to nontreated diabetic and nondiabetic spontaneously hypertensive rats. The total urinary kallikrein levels were significantly raised in captopril-treated diabetic and nondiabetic spontaneously hypertensive rats against the values obtained from nontreated diabetic and nondiabetic spontaneously hypertensive rats. These results indicate that blood pressure reduction and left ventricular wall regression with captopril treatment might be due to enhanced renal kallikrein formation. The significance of these findings is discussed.