Prostaglandins and the lung

The regulatory function of prostaglandins (PGs) in virtually every organ system is unusual because the metabolic pathways by which these fatty-acid autacoids are formed and the manner in whih they influence function seem to be controlled largely by the individual organ itself. Thus, the metabolic state of the organ may alter biosynthetic pathways locally, thereby changing the PG metabolite formed and its function within the organ. Although the lung is one of the major sites of PG synthesis and inactivation, this organ, in the intact state, is relatively inaccessible to investigation. Moreover, the continuous interaction of its respiratory, vascular, and metabolic functions imposes formidable barriers to the investigation of the effects of these autacoids. The PG may affect each of these lung functions in separate and sometimes opposite directions. Understanding is further hampered by the necessity of evaluating these interacting functions as they relate to one another while they are being affected by the PGs. In humans, most studies have been directed, necessarily, toward the effects of PGs on respiration. The effects of these autacoids on the human pulmonary vascular bed have not been systematically studied. Most investigators studying the effects of PGs on the lung have used animals with thoracotomy and cannulated lobar vessels and bronchi, and others have studied PGs in excised lung lobes or in the isolated vessels and bronchi suspended in a smooth-muscle bath. These cotributions have sometimes been accepted with reservation because alterations in the physiologic state of the lung after surgical procedures necessarily involving injury to blood and lymph vessels and nerves as well as other interventions may alter PG metabolism. The extent to which interventions may obscure the effects of PGs on the lungs of intact animals has not received adequate attention. The problem is further complicated by the demonstrated ability of potent PG-synthesis inhibitors themselves to cause alterations in pulmonary vascular resistance. This review of the state of the art is directed primarily toward an evaluation of the response of the pulmonary vascular bed to PG precursors, intermediates, and metabolites. The effect of these agents on lung function is presented in relation to their effect on vascular responses to these substances. The following four topics are discussed in turn: 1) Pathways of PG synthesis and metabolism, 2) Reactivity of the pulmonary vascular bed and airways to prostanoids [Arachidonic acid, the PG precursor; Dihimo-γ-linolenic acid, a sparse precursor; PG endoperoxides; PGs; Thromboxanes; Prostacyclin (PGI₂)], 3) Relative potency of prostanoids and other substances in the pulmonary vascular bed, PGs in diseases of the lung. Although a large body of experimental data has been published on the PGs to date, relatively few therapeutic indications have evolved. Therapeutic application of these autacoids is hampered by our incomplete understanding of their role in health and disease. Current studies in intact animal species have been consistent in some instances with in vitro observations, as with the primary PGs, but marked differences prohibit direct application of experimental data to human disease. Experimental studies have served to advance our understanding of pulmonary physiology. (273 references.)