The role of histamine and other mediators in microvascular changes in acute inflammation

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Abstract
In addition to bronchial smooth muscle, histamine and other mediators act in bronchial asthma on the microcirculation of pulmonary connective tissue. The mediators induce enhanced blood flow, and by acting on the blood–tissue barrier, they induce increase in vasopermeability with edema and in more severe injury microhemorrhage and microthrombosis and infiltration of the connective tissue by leukocytes, predominantely neutrophils. The scheme proposed 10 years ago by K. F. Austen and co-workers in 1976 still holds true: a short-acting humoral–cellular phase is followed by a longer-acting pathopharmacologic or inflammatory phase. Some mediators, including histamine, serotonin, bradykinin, the sulfido leukotrienes and platelet activating factor, have a direct effect on endothelium and smooth muscle cells and more severe injury is due to mediators that exert their effect via neutrophils, which release lysosomal constituents. The intact complement-derived fragments C3a and C5a act directly and for a short period, as do histamine and the other direct-action mediators. The accumulation of neutrophils is brought about by C5a and its stable derivative C5ades Arg, leukotriene B4, PAF, and interlcukin-1. Unlike the direct-action mediators, whose effect on the microcirculation does not extend beyond 20–25 min, those mediating via neutrophils have a delayed effect (peak 1–2 h), which parallels the neutrophil influx. The direct action mediators exert their effects on the microcirculation also in neutropenic animals. The most potent agents causing enhanced blood flow are the prostaglandins of the E class. Through the enhanced blood flow increase in vasopermeability, neutrophil emigration and hemorrhage are enhanced. Concerning mechanisms, histamine and other direct-action mediators induce subtle changes, characterized by interendothelial gaps in postcapillary venules and no visible endothelial injury. Neutrophil lysosomes, in concert with oxygen radicals, cause a degradation of subendothelial and perivascular matrices, including basement membranes and fragmentation of endothelium. The entire microcirculation is effected, but primarily the postcapillary venules. The described changes markedly influence the changes taking place in the airways.