PAF molecular heterogeneity: pathobiological implications.

The existence and potential (patho)physiologic significance of PAF molecular heterogeneity can no longer be summarily dismissed or ignored. While significant advances in the chemistry of PAF have been made, the (patho)physiologic behaviors of most of the PAF molecular species of biologic origin await further study. This is because to date, investigators have studied the biologic activities of what was previously thought to be PAF, i.e., only 16:0- and 18:0-AGEPC. In view of the evidence presented in this review, a comprehensive investigation of the possible biologic relevance and significance of PAF molecular heterogeneity is warranted. Hopefully, such studies will be designed to elucidate the extent to which the various molecular species of PAF differ in their intrinsic in vitro and in vivo (patho)physiologic behaviors (agonistic, synergistic, and possibly antagonistic) and modes of action. Once this additional information has been derived, the pathobiologic relevance of this class of phospholipid autacoid may be better understood.

Cardiopulmonary and intravascular alterations during the sustained infusion of PAF.

The physiologic responses during prolonged exposure to platelet activating factor (PAF) are largely unexplored. Thus, the cardiopulmonary and intravascular effects of a sustained infusion of 1-O-hexadecyl-2-acetyl-sn-glycero-3- phosphocholine (C16:0-AGEPC; 0.159 nmole/kg/min for 120 min) were characterized in anesthetized rabbits. Within minutes, a transient period of tachypnea developed and was followed by 30 min of stable ventilation. Subsequently, both respiratory rate and tidal volume irreversibly increased. The latter pulmonary ventilatory alterations were preceded by lung mechanical changes, i.e., dynamic lung compliance (CLdyn) decreased 21.6 +/- 3.4% (mean +/- SE) and total pulmonary resistance (Rpulm) increased 25.1 +/- 8.5%. In contrast to CLdyn which partially recovered during infusion, Rpulm remained elevated throughout the study, Concurrent with these pulmonary alterations, significant cardiovascular changes also occurred. Right ventricular hypertension developed immediately and was maximal within 7.9 +/- 0.9 min; this hypertension persisted throughout the infusion period but rapidly reversed thereafter. Mean arterial pressure (MAP) decreased 37.1 +/- 5.8% within 31.4 +/- 2.5 min and then remained at this level. The patterns and extent of alterations in left ventricular pressure, +dP/dtmax, and -dP/dtmax paralleled the changes in MAP and were accompanied by a progressive decrease in left ventricular end-diastolic pressure. These cardiopulmonary effects of C16:0-AGEPC developed in association with prolonged thrombocytopenia and intravascular platelet activation. In contrast, C16:0-AGEPC-induced neutropenia at 5 min was reversed within 60 min and was followed by sustained neutrophilia. In combination, these data suggest that the continuous biosynthesis and release of PAF in vivo could modulate significant, persistent pathophysiological alterations.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet activating factor in pulmonary pathobiology.

Platelet activating factor (PAF) is a potent phospholipid mediator of inflammation that has been gaining increasing attention because of its pathophysiologic effects upon the lung. In particular, PAF stimulates pulmonary hypertension, ventilatory alterations, bronchoconstriction, airway hyperreactivity, and pulmonary inflammatory cell accumulation and edema in a variety of experimental animals and in humans. These observations promote the speculation that this unique phospholipid likely is involved in similar tissue responses during the course of human lung disease. The use of specific PAF antagonists should expand our understanding of these processes and may be useful in treating or preventing PAF-mediated pulmonary disorders in the future.

Mechanism of functional residual capacity increase in haemorrhagic shock.

Shock was elicited in anaesthetized dogs by maintaining a haemorrhagic hypotension of 4 kPa until 30 per cent spontaneous refusion, followed by total reinfusion. Functional residual capacity (FRC) and minute ventilation increased considerably similarly to our previous experiments. Lactate content in both the external intercostal and the biceps femoris muscles increased significantly in advanced shock. The expiratory external abdominal oblique muscle showed electromyographic signs of fatigue. At the height of the FRC changes tonic contraction of the external intercostal muscle could be demonstrated electron microscopically. This tonic contraction is the main factor in the large FRC rise in late shock forming the basis of a hitherto unknown vicious circle.

Increase of functional residual capacity in hemorrhagic shock.

Functional residual capacity (FRC) was measured by body plethysmography in anesthetized dogs subjected to hemorrhagic shock. This was elicited by bleeding the animals to a mean arterial blood pressure of 4 kPa. Reinfusion was done at 30% spontaneous uptake of the maximal bleeding volume. During the initial rapid bleed-out and early hypovolemia, the FRC increased proportionally to the bleeding volume by an average factor of 0.19. Subsequently FRC increased further to about 50% above the control level, and it remained elevated even after reinfusion. Minute ventilation reached a peak value of about 2.5 times of that of the control state, and then declined to almost control values in late hypovolemia when FRC was still very high. The mechanism of the significant increase in FRC is not clear, but it is suggested that the balance of its effects is unfavorable to the maintenance of adequate ventilation in late shock.