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Biomedical subjects

H S Jacob

Publications and source records attributed to H S Jacob.

At least 127 records · Page 7Linked to original sources
PubMed1981

Rapid in vivo clearance of C5ades arg: a possible protective mechanism against complement-mediated tissue injury.

C5ades arg is an important mediator of the tissue injury associated with intravascular complement activation and exerts its effects by causing granulocyte aggregation, leukoembolism, and oxidative damage to endothelial cells. We have now investigated some of the mechanisms responsible for deactivation of this potent complement fragment by studying the clearance of C5ades arg from the plasma of New Zealand white rabbits in vivo. Quantitative aggregation of human granulocytes was used as a bioassay for rabbit C5ades arg. After a bolus intravenous infusion of activated autologous plasma complement, athe plasma C5ades arg content peaked within 60 sec and was cleared rapidly and exponentially, with a mean half-life of 3.0 +/- 0.6 (S.E.M.) min. In neutropenic animals the half-life of C5ades arg was prolonged by 57% +/- 22 and splenectomy, but not hepatectomy, also significantly lengthened the half-life by 48% +/- 18. The most striking delay in C5ades arg clearance was induced by inhibition of endogenous proteases with EACA and aprotinin, which prolonged the half-life by 87% +/- 4 and 94% +/- 12, respectively. These data demonstrate that like other complement fragments such as C3a, C5ades arg has a very brief functional half-life in experimental animals and that although other mechanisms may be operative, endogenous proteases, circulating granulocytes, and the spleen may be important in deactivating this biologically important complement fragment. Impairment of these and other clearance mechanisms could lead to prolonged and excessive complement activation and subsequent exaggerated tissue injury.

Agranulocytosis↗
PubMed1981

Sudden blindness in acute pancreatitis. Possible role of complement-induced retinal leukoembolization.

During an episode of acute alcoholic pancreatitis, severe visual loss and the funduscopic appearance of Purtscher's retinopathy-a syndrome thought to be caused by posterior retinal microembolization-developed in a patient. We propose that emboli in this case may have consisted of aggregated granulocytes since plasma samples from eight to 12 patients with subsequently studied acute pancreatitis caused granulocyte aggregation in vitro. The aggregant was demonstrated to be an activated fragment of the complement system, derived from C5. Since we could generate identical granulocyte aggregating activity by treating serum or purified C5 with trypsin, we suggest that proteases released from an inflamed pancreas might have produced a C5-derived aggregant in this case, as well as in three other previously reported cases of acute pancreatitis and Purtscher's retinopathy. We conclude that complement-induced leukoembolization may be a previously unsuspected cause of vital-tissue damage.

Acute Disease↗
PubMed1981

Complement-induced granulocyte aggregation in vivo.

Previous studies from our laboratories have demonstrated that granulocytes (PMNs), when exposed to activated complement (C) (specifically C5a), will aggregate and be provoked to damage cultured endothelial cells in vitro; it was postulated that these phenomena might also occur in vivo, constituting a previously unsuspected mechanism of immune tissue damage. The studies here presented confirm by intravital microscopy that PMN aggregation and leukoembolization in fact occur in live animals when C is activated or C5a is infused, and that these are accompanied by extravasation of plasma proteins in a pattern suggesting endothelial damage. It is concluded that altered microvascular behavior of PMNs is a possible pathogenetic mechanism in disease states associated with C activation.

Animals↗
PubMed1980

Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value.

Clinical and experimental observations suggest that aggregation of polymorphonuclear granulocytes (PMN) in response to activated complement (C) might contribute to the genesis of the adult respiratory distress syndrome (ARDS), aggregating PMN causing pulmonary dysfunction by becoming lodged in the lung as leucoemboli. PMN-aggregating activity can be detected in C-activated plasma and reflects C5a levels. In 61 patients at risk for ARDS a strong and highly significant correlation was found between the presence of PMN-aggregating activity in the plasma and the development of ARDS; this correlation was also significant when patients with sepsis were excluded from analysis. In patients followed prospectively detection of elevated C5a seemed to be a useful predictor of ARDS. Since corticosteroids have been shown to inhibit PMN aggregation both in vitro and in vivo, the evidence for a role for PMN aggregation in the genesis of ARDS supports the use of corticosteroids in this disorder.

Cell Aggregation↗
PubMed1980

Abnormal adherence of sickle erythrocytes to cultured vascular endothelium: possible mechanism for microvascular occlusion in sickle cell disease.

The abnormal shape and poor deformability of the sickled erythrocyte (RBC) have generally been held responsible for the microvascular occlusions of sickle cell disease. However, there is no correlation between the clinical severity of this disease and the presence of sickled RBC. In searching for additional factors that might contribute to the pathophysiology of sickle cell disease, we have investigated the possibility that sickle RBC might be less than normally repulsive of the vascular endothelium. After RBC suspensions are allowed to settle onto plates of cultured human endothelial cells, normal RBC are completely removed by as few as six washes. In contrast, sickle RBC remain adherent despite multiple washes. On subconfluent culture plates, normal RBC are distributed randomly, whereas sickle RBC cluster around endothelial cells. Sickle RBC adherence is not enhanced by deoxygenation but does increase with increasing RBC density. The enzymatic removal of membrane sialic acid greatly diminishes the adherence of sickle RBC to endothelial cells, suggesting that sialic acid participates in this abnormal cell-cell interaction. Although net negative charge appears normal, sickle RBC mainfest an abnormal clumping of negative surface charge as demonstrated by localization of cationized ferritin. These abnormalities are reproduced in normal RBC loaded with nonechinocytogenic amounts of calcium. We conclude that sickle RBC adhere to vascular endothelial cells in vitro, perhaps caused by a calcium-induced aberration of membrane topography. This adherence may be a pathogenetic factor in the microvascular occlusions characteristic of sickle cell disease.

Anemia, Sickle Cell↗
PubMed1980

Complement-induced vascular leukostasis. Its role in tissue injury.

The plasma complement system evolved as a beneficial antimicrobial mechanism. However, this system can be activated chaotically in such situations as extracorporeal perfusion, trauma, sepsis, or acute pancreatitis. When so activated, the complement component C5a may aggregate granulocytes and cause leukoembolization; it is suggested that such leukoembolization is an important, previously unsuspected mechanism of tissue damage. In addition, toxic oxygen species, such as superoxide, that are produced by granulocytes that have been triggered by C5a can damage the endothelium, an event that may, if it occurs in the lungs, contribute to the development of the adult respiratory distress syndrome (ARDS). Hence the previously empiric use of high doses of corticosteroids in treating shock states, particularly in cases of the ARDS, may have a physiologic basis since very high concentrations of such drugs have been shown to inhibit both superoxide production and granulocyte aggregation.

Acute Disease↗
PubMed1980

Granulocyte aggregometry: a sensitive technique for the detection of C5a and complement activation.

We have previously shown that complement (C) activated plasma causes granulocyte (PMN) aggregation in vitro and that C5a is responsible. The C-induced aggregation of PMNs treated with cytochalasin-B (CB) is markedly enhanced and irreversible, and the magnitude of the response is proportional to the log (concentration of activated plasma), allowing use of this technique to detect C5a and hence C-activation. To compare the sensitivity of granulocyte aggregometry to that of more standard methods of detecting C-activation, we produced graded C-activation in vitro by treating fresh serum with varying amounts of zymosan. Aggregometry was the most sensitive index of C-activation, detecting C-activation, produced by 0.02 mg zymosan/ml of serum--1/10 that required to produce C-activation detectable by C3 immunoelectrophoresis (the next most sensitive technique). Granulocyte aggregometry may also be used to detect in vivo C-activation. We have found aggregating activity in plasmas from patients with systemic lupus erythematosus, immune vasculitis, transfusion reactions, and other conditions associated with in vivo C-activation, but not in the plasmas of normal subjects.

Cell Aggregation↗
PubMed1979

Corticosteroids inhibit complement-induced granulocyte aggregation. A possible mechanism for their efficacy in shock states.

Granulocyte (PMN) aggregation and embolization may underlie complement (C)-mediated organ dysfunction in such syndromes as hemodialysis neutropenia and Purtscher's ischem;c retinopathy. Because of clinical and pathologic parallels, we have further suggested a role for this phenomenon in the genesis of the adult respiratory distress syndrome (ARDS). Because corticosteroids are commonly used in immune diseases, and have particularly been claimed efficacious in shock and ARDS, we tested the capability of methylprednisolone (MP), hydrocortisone (HC), and dexamethasone (DEX) to inhibit PMN aggregation. Aggregation engendered in vitro by zymosan-activated plasma (ZAP) was inhibited by MP and HC at concentrations approximating plasma levels achieved with the large bolus (30 mg/kg i.v) therapy advocated in shock states; DEX was almost without effect. Using intravital fluorescence microscopy, we observed PMN aggregation and embolization in the mesenteric vessels of rats given intra-arterial infusions of ZAP; this was also prevented by pretreatment with 30 mg/kg MP. Steroid inhibition of aggregation seemed not to involve disruption of receptor function, because aggregation induced by alternative agents, n-formyl-Met-Leu-Phe and the ionophore A23187, was also inhibited by MP. Moreover, corticosteroid inhibition of PMN prostaglandin synthesis is also an unlikely explanation for our results, since aspirin and ibuprofen failed to block aggregation and arachidonic acid neither effected aggregation itself nor ameliorated the steroid effect. Our studies provide a plausible rationale for the empiric observation that high-dose corticosteroids may benefit patients with syndromes associated with microvascular leukostasis.

Cell Aggregation↗
PubMed1979

Modulation of neutrophil function by lysozyme. Potential negative feedback system of inflammation.

Host responses to infectious organisms should be modulated so that tissue-damaging products of inflammatory cells do not produce excessive destruction of normal tissue. Lysozyme, which is continuously secreted by monocytes, which, in turn, migrate relatively late to inflammatory areas, was found to significantly dampen several responses of neutrophils to inflammatory stimulants. Thus, human lysozyme obtained and purified from the urine of patients with monocytic leukemia (but not its structurally similar and comparably cationic analogue, eggwhite lysozyme) depresses chemotaxis of normal neutrophils to activated complement, bacterial supernate, and N-formylmethionyl-phenylalanine. In addition, human (but not eggwhite) lysozyme depresses oxidative metabolism (hexose monophosphate shunt activity) and superoxide generation of neutrophils. The specificity of the suppressive effects was indicated by inhibition studies with rabbit antihuman lysozyme antibody, and with the trisaccharide of N-acetylglucosamine, a specific inhibitor of lysozyme. The results suggest that lysozyme, a product of inflammatory cells themselves, may function in a negative feedback system to modulate the inflammatory response.

Cell Migration Inhibition↗
PubMed1979

Granulocyte aggregation as a manifestation of membrane interactions with complement: possible role in leukocyte margination, microvascular occlusion, and endothelial damage.

Activation products of the terminal complement cascade potently affect granulocyte function, inducing, for example, their migration toward (chemotaxis), and adherence to (opsonization), microbes, and stimulating their production of microbicidal oxygen radicals such as superoxide anion, and the like. We present studies that demonstrate that a C5-derived peptide, probably C5a, is a potent promoter of granulocyte and monocyte adhesion to endothelium (margination) and, in addition, causes granulocyte autoaggregation in vitro and in vivo. Although possibly beneficial by producing phagocyte clumps to mechanically entrap unwanted microbes, such aggregates may be deleterious, particularly if sustained, especially in the lung.

Animals↗
PubMed1978

Extreme but asymptomatic carboxyhemoglobinemia and chronic lung disease.

Carboxyhemoglobinemia is a well-known consequence of carbon monoxide exposure from smoking. However, only moderately elevated levels have been reported. We report the case of an asymptomatic man with severe chronic obstructive lung disease and carboxyhemoglobin levels repeatedly in excess of 30% (maximum, 38.0%) due to smoking. The mechanism by which such high levels were attained was primrily a combination of arterial hypoxia and a high carbon monoxide yield from tobacco. For a given level of carbon monoxide exposure, the hypoxic person will attain a higher carboxyhemoglobin level than will a person without hypoxia.

Aged↗