Role of Humoral Mediators in Adult Respiratory Distress Syndrome

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today'S practice 01 cardiopulmonary medicine

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Role of Humoral Mediators in Adult Respiratory Distress Syndrome* Herbert B. Hechtman, M.D.; C. Robert Valeri, M.D.;t and David Shepro, Ph.D.t.

to the parenchyma and microvasculature of the I njury lungs underlies the adult respiratory distress syn-

drome. Patients present with a rapidly progressive impairment in respiratory gas exchange, manifest by hypoxia and increases in physiologic shunting (Qs/QT), and physiologic dead space (VDNT). Inspiratory pressure rises as compliance falls. There is an increase in pulmonary vascular resistance and pulmonary arterial pressure. The fact that the pulmonary arterial wedge pressure is normal while the chest x-ray film shows pulmonary edema suggests that there is an increase in microvascular permeability, causing low pressure edema. Injurious agents can act directly or indirectly on the lungs. Examples of direct injury are inhaled acid, which results in protein denaturation, or, secondly, pulmonary emboli which obstruct the pulmonary vasculature and lead to pulmonary hypertension. Indirect effects are common and relate to a variety of vasoactive and bronchoactive agents released or secreted by many tissues and cells. Longer term and more devastating pulmonary injury may be due to inflammatory reactions which are inappropriately recruited. The release of inflammatory mediators from tissue or circulating white blood cells (WBCs) may in turn lead to widespread damage. Thus, bacteremia and experimental endotoxemia are causes of generalized organ failure, including the adult respiratory distress syndrorne.' The WBC is thought to playa central role. SEROlONIN (5-HYDROXYTRYPTAMINE, 5-HT)

This vasoactive amine has the capacity to cause pulmonary arterial constriction, as well as generalized ·From the Department of Surgery, Brigham and Women's Hospital and Harvard Medical School; and the Naval Blood Research Laboratory, Boston University School of Medicine, the Biological Science Center, Boston University, Boston. Supported in part by the National Institutes of Health grants GM24891-06 and HL16714-OB, by the US Navy Office of Naval Research contract NOOO14-79-C-Ol68, by the Brigham Surgical Group, Ine., and by the Trauma Research Foundation. tNaval Blood Research Laboratory, Boston University. +Biological Science Center, Boston University. Reprint requests: Dr. Hechtman, Brigham and Womens Hospital, 75 Francis Street, Boston 02115

bronchospasm, including peripheral bronchioles. The highest concentrations of serotonin outside of the intestine are contained in the dense bodies of platelets. Platelet entrapment, activation, and release in the lungs is therefore likely to result in high local concentrations of serotonin. The effects on pulmonary function can be significant; for example, after experimental pulmonary embolism in the dog, the rise in mean pulmonary arterial pressure to 30 mm Hg can be reduced to 20 mm Hg by blocking serotonin receptors with ketanserin." Further, QsQr is lowered from 31 percent to the preembolism baseline value of 9 percent, suggesting that in experimental pulmonary embolism, serotonin is the principal determinant of bronchospasm and the decreased ventilation-perfusion ratio (Fig 1). Although the serotonin content of platelets in man is one third that of the dog, the effects of embolism are believed to be qualitatively similar. In the first one to two days of the adult respiratory distress syndrome, patients entrap platelets and release serotonin into their lungs. Treatment with serotonin antagonists at this early point may be beneficial." Ketanserin infused intravenously can substantially reverse the rise in (Qs/Qr). Furthermore, the reductions of mean pulmonary arterial pressure and peak inspiratory pressure, although more modest, are still significant. Aspiration of acid induces microembolization. Five minutes after experimental aspiration localized to one lung, severe thrombocytopenia develops. Intravascular platelet aggregates are observed in blood smears, and there is generalized pulmonary and systemic entrapment of platelets labelled with radioactive indium-lll (unpublished data). This is temporally associated with an increase in (QS/QT), in both aspirated and nonaspirated lungs (Fig 2). After aspiration, pulmonary hypertension develops over the course of several hours. The rise in mean pulmonary arterial pressure can be reversed by serotonin inhibition with ketanserin. Serotonin not only constricts arterioles, but also postcapillary venules," an event which could raise pulmonary microvascular pressure. Inhibition of serotonin not only CHEST I 86 I 4 I OCTOBER. 1984

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leads to a decline in hydrostatic pressure, but there is also a substantial reduction in the volume of pulmonary edema formed after aspiration. That this reduction in edema is related to a decline in pulmonary hydrostatic pressure can be seen by the fact that the nonselective dilator, nitroprusside, also reduces pulmonary pressure, as well as the volume of edema. Nitroprusside was less effective than ketanserin and, in the dose required to lower mean pulmonary arterial pressure, led to severe systemic hypotension. PLATELET ACTIVATING Fxcroa Platelet entrapment in the lungs after pulmonary embolization is likely due to the interaction of circulating platelets with thrombin in the clot. A number of other clinical and experimental states are associated with platelet sequestration; however, the mechanism of these platelet interactions are often obscure. Platelet activating factor, a recently described and synthesized glycerol phosphorylcholine, may play an

important role in platelet activation. Platelet activating factor is synthesized by alveolar rnacrophages," probably in response to airway stimuli such as acid aspiration. Experimentally, an intravenous bolus of synthetic platelet activating factor has the capacity to induce severe, but reversible, thrombocytopenia and leukopenia," along with circulatory collapse? and WBC accumulations and edema in the lungs." Platelet activating factor, by virtue of its WBC interactions, may underly a number of obscure cardiopulmonary disorders. Thus, platelet activating factor can both activate and be synthesized by circulating WBC S9 in response to a variety of stimuli. The interaction of complement components with WBCs has been related to the adult respiratory distress syndrome." The fragment C5a stimulates WBCs to release a variety of inflammatory mediators. One of these agents is platelet activating factor, which itself is a potent vasoconstrictor, chemoattractant, and

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2. Following localized aspiration of acid, physiologic shunting is prominent in both aspirated and nonaspirated lungs. This is temporally related to generalized entrapment of platelets. Physiologic shunt was measured by sampling blood from pulmonary artery and pulmonary veins of both lungs. FIGURE

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MINUTES HumoralMediators In ARDS (Hechtman, vaJerl, ShepfO)

inducer of microvascular permeability. 9.10 It is possible that other agents, such as bacterial endotoxins in sepsis or proteolytic enzymes in acute pancreatitis, induce synthesis of platelet activating factor from circulating WBCs via a C5a intermediary. u.iz Pulmonary parenchyma contains complement components; for example, C5 can be recovered by bronchoalveolar lavage." It is likely that the complement system, either locally in the lung or in plasma, is active in the sequence leading to the adult respiratory syndrome; however, the primacy of this action is debated. Complement may simply amplify the inflammatory sequence. LEUKOCYTES

Agreement is general that leukocytes and their products are principal mediators of the adult respiratory distress syndrome. These inflammatory cells may be entrapped in the lungs in large numbers." Their importance is inferred from their strategic histologic location in proximity to damaged lung. 15 Furthermore, experimental depletion of WBCs protects animals from developing high protein pulmonary edema following challenge with agents such as activated complemerit" or endotoxin." Similar protective effects of WBC depletion have been observed in the settings of glass-bead microembolization," air embolism," or thrombin infusion;" Granulocytes have also been implicated in the pathogenesis of pulmonary oxygen toxicity," however; a central role for leukocytes has not been shown in all studies of the adult respiratory distress syndrome. Thus, the hemodynamic and blood gas exchange abnormalities after endotoxemia in baboons or ethchlorvynol administration in dogs is not prevented by leukopenia'f" The interpretation of these two studies must be done cautiously because of questions regarding the adequacy of neutrophil depletion, as well as the toxicity of the depletion process itself

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positive two hours after aspiration, indicating entrapment. This event was prevented by treatment with imidazole derivative, ketoconazole.

fact that thromboxane A2 is synthesized by pulmonary parenchyma, WBCs, the vasculature." and also by endothelium" argues that it may play a role in chemotaxis during the adult respiratory distress syndrome. The role of thromboxane A2 in experimental aspiration of acid is illustrative. Two hours following aspiration, WBCs are entrapped in the lungs (Fig 3). Treatment with ibuprofen, which blocks cyclooxygenase, or ketoconazole, an imidazole derivative which blocks thromboxane synthetase, prevents a rise in circulating thromboxane A2 , as well as leukosequestration.":" There is a marked reduction in the amount of pulmonary edema (Fig 4), as well as in the inflammatory cell infiltrate seen histologically. The decline in edema is not dependent on lowering pulmo-

CHEMOTAXIS

Events which initiate the adult respiratory distress syndrome are thought to involve the generation of chemoattractants which cause WBCs to localize in the lungs. The lungs produce several types of chemoattractants. Platelet activating factor occupies a central role, both acting as a chemoattractant" and stimulating synthesis of others. Thus, mast cells can be triggered by platelet activating factor to produce the lipoxygenase derivatives, hydroxyeicosatetraenoic acid and leukotriene B... 24 Mast cells may also be activated by other events such as immunologic reactions to produce these same chemoattractants. The proteolytic enzymes which might be generated and released from stimulated WBCs could activate complement, leading to a local increase in the concentration of another potent chemoattractant, C5a. Finally, thromboxane A2 has been found to promote WBC adhesiveness." The

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FIGURE 4. In untreated control dogs, edema was first noted 2Y2 hours after acid aspiration. Volume of fluid collected from endotracheal tube was significantly reduced by use ofketoconazole.

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nary pressures, since the mean pulmonary arterial pressure and pulmonary arterial wedge pressure are unchanged. TOXIC WBC PRODUCTS A number of recent studies describe several potent products of neutrophils which could cause reversible, as well as permanent, tissue injury and altered hemodynamics. These toxic WBC agents are useful in normal, contained bactericidal processes. Their importance is illustrated by the susceptibility of patients to recurrent infections who have genetic defects in WBC production of oxygen radicals (chronic granulomatous disease) or in the production and release of granular enzymes from WBCs; however, the extracellular release of these WBC toxins can be injurious to surrounding cells. This coupled with an uncontrolled recruitment of WBCs is thought to be an important mechanism of pulmonary injury, and perhaps of multisystem organ failure. An uncontrolled inflammatory reaction can be triggered by localized aspiration ofO.IN HCl. This results in infiltration of inflammatory cells in both aspirated and nonaspirated pulmonary segments (unpublished data). After three hours the microscopic picture of hemorrhagic pulmonary edema and pneumonitis in aspirated and nonaspirated sides is indistinguishable. The severity of the reaction is principally determined by the distribution of blood flow; the lower lobes with their increased flow have a greater inflammatory reaction than the upper lobes. The consequences of localized aspiration are observed not only in the lungs, but also systemically. Hypotension and low cardiac output, as well as generalized organ congestion and edema, are prominent features. Proteases originating from WBCs are important mediators of pulmonary injury. These proteases can damage pulmonary tissue and increase permeability by direct action on the vascular basement membranes, elastin, collagen, or other structural elements. In addition, proteases such as elastase can lead to microvascular permeability by activation of components of the contact or complement systems. The importance of elastase in the adult respiratory distress syndrome is suggested by the finding of elastase activity in bronchoalveolar lavage of patients suffering from the syndrome." Furthermore, if the lavage fluid did not contain free enzyme, an inhibitor of elastase, either Qlantiproteinase inhibitor or Q2-macroglobulin was demonstrable. Activated neutrophils not only release proteolytic enzymes, but also generate oxygen metabolites including superoxide (02-), hydrogen peroxide, and perhaps the hydroxyl radical. There is abundant experimental evidence showing that WBC-mediated pulmonary damage can be prevented by infusing superoxide dis828

mutase and catalase. 30 This supports the thesis that O2 and hydrogen peroxide are injurious, since superoxide dismutase is the primary defense against O 2- , catalyzing the following reaction: 02- + 02- + 2H+ ...... H202 + O2 Furthermore, in the absence of catalase, hydrogen peroxide may be degraded to the very reactive hydroxyl radical. OxYGENATION PRODUcrS OF ARACHIDONIC ACID

The salutary effects of antioxidants may not only be due to their scavaging of toxic free radicals, but may also relate to their possible inhibition of arachidonic acid metabolism. Initial steps in the oxygenation of arachidonic acid involves cyclooxygenation and lipoxygenation leading to the generation of peroxy radicals." Antioxidants may modify this step and reduce synthesis of agents that may play important roles in the adult respiratory distress syndrome such as leukotriene and thromboxane ~. The leukotrienes have a marked action on smooth muscle, being thousands of times more potent than histamine. Leukotriene C.. and leukotriene D.. have a selective action on the small airways of lungs. Furthermore, they provoke increases in systemic permeability in picogram quantities. Their role in the adult respiratory distress syndrome remains putative, since a sensitive assay is not yet available to prove an increase in leukotriene concentration. In addition, pharmacologic inhibitors of leukotriene such as the receptor antagonist, FPL 55712, have not been widely applied to studies of the adult respiratory distress syndrome. Preliminary data suggest that FPL 55712 will significantly modify the formation of pulmonary edema following aspiration of acid without preventing leukosequestration in the lungs (unpublished data). Furthermore, edema fluid that issues from the endotracheal tube of acid-aspirated animals will induce increased permeability in a hamster cheek pouch, as well as when bioassayed in the skin of a guinea pig. These permeability effects can be prevented by pretreating the bioassay animal with FPL 55712. Pure leukotriene C.. and leukotriene D.. induce increases in permeability which can be modified by FPL 55712. Thromboxane ~ is involved in this permeability sequence, since pretreatment of the leukotriene-challenged bioassay animal with a thromboxane synthetase inhibitor or thromboxane receptor antagonist will reduce permeability," Finally, pretreatment with a thromboxane inhibitor of a bioassay animal, challenged with edema fluid from an aspirated animal, will also prevent permeability changes. The beneficial effects of thromboxane inhibition in modifying the edema of acid aspiration" and thrombininduced microembolism" are clear, but the mechanisms must still be resolved. It is likely that thromboxHumoral Mediators In ARCS(Hechtman, Valeri, ShepfO)

ane plays a role in chemotaxis, as well as in permeability, although its actions may be indirect. Thromboxane is also involved in the cardiovascular instability associated with aspiration, perhaps because of the secondary generation of a circulating negative inotropets)." Thromboxane ~ is also a strong smooth muscle constrictor; however; it is not the cause of the pulmonary hypertension of aspiration. In other settings, it may be an active pulmonary vasoconstrictor, such as immediately following the experimental infusion of endotoxin. At this time, but not later in the course of endotoxemia, thromboxane inhibitors prevent the rise in mean pulmonary arterial pressure." In summary, a variety of injurious agents can stimulate an uncontrolled and generalized inflammatory reaction. Circulating mediators carried in platelets, and particularly in leukocytes, can lead to generalized pulmonary injury, as well as cardiovascular failure. Modification of this self-destructive inflammatory response can be done at a number of points and promises new directions in the pharmacologic control of the adult respiratory distress syndrome. REFERENCES 1 Vito L, Dennis R, Weisel RD, Hechtman HB. Sepsis presenting as acute respiratory insufficiency. Surg Gynecol Obstet 1984; 138:896-900 2 Huval wv, Mathieson MM, Stemp LI, Dunham BM, Jones AG, Shepro D, et ale Therapeutic benefits of 5-hydroxytryptamine inhibition following pulmonary embolism. Ann Surg 1983; 197:220-25 3 Huval wv, Lelcuk S, Shepro D, Hechtman HB. Role of serotonin in patients with acute respiratory failure. Ann Surg (to be published) 4 Bhattacharya J, Nanjo S, Staub NC. Micropuncture measurement of lung microvascular pressure during 5HT infusion. J Appl Physiol Respir Environ Exercise Physiol 1982; 52:634-37 5 Arnoux B, Durand J, Rigaud M, Vargaftig BB, Benveniste J. Release of platelet activating factor (PAF-acether) and arachidonic acid metabolites from alveolar macrophages. Agents Actions 1981; 11:555-56 6 McManus LM, Pickard RN, Fitzpatrick FA, O'Rourke RA, Crawford MH, Hanahan DJ. Acetyl glyceryl ether phophorylcholine: intravascular alterations following intravenous infusion into the baboon. Lab Invest 1981; 45:303-07 7 Bession R, Bonnett J, Apffel D, Soulard C, Desgroux L, Pelas I, et ale Acute circulatory collapse caused by platelet activating factor (PAF-acether) into dogs. Eur J Pharmacoll983; 86:403-13 8 Worthen GS, Goins AJ, Mitchel BC, Larsen GL, Reeves JR, Henson PM. Platelet-activating factor causes neutrophil accumulation and edema in rabbit lungs. Chest 1983; 83:135-53 9 Lynch JM, Lotner GZ, Betz SJ, Henson PM. The release of a platelet-activating factor by stimulated rabbit neutrophils. J Immunol 1979; 123:1219-26 10 Jacob HS, Craddock PR, Hammerschmidt DE, Moldow CF: Complement-induced granulocyte aggregation: an unsuspected mechanism of disease. N Eng} J Med 1980; 302:789-803 11 Hammerschmidt DE, Weaver LJ, Hudson LD, Craddock PRN, Jacob HS. Association of complement activation and elevated plasma cSa with adult respiratory distress syndrome. Lancet 1980; 1:947-49 12 Solomkin JS, Cotta L, Hurst JM, Joffe SN. Does complement activation in acute pancreatitis result in respiratory failure. Surg Forum 1983; 34:17-20

13 Kolb WD, Kolb LM, Wetsel RA, Rogers WR, Shaw JD. Quantitation and stability of the fifth component of complement (C5) in bronchoalveolar lavage fluids obtained from non-human primates. Am Rev Respir Dis 1981; 123:226-31 14 Huval wv, Dunham BM, Lelcuk S, Valeri CR, Shepro D, Hechtman HB. Thromboxane mediation of cardiovascular dysfunction following aspiration. Surgery 1983; 94:259-66 15 Repine JE, Bowman M, Tate RM. Neutrophils and lung edema. Chest 1982; 81:475-505 16 Craddock PR, Fehr J, Brigham KL, Kronenberg RS, Jacob HS. Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis. N Eng} J Med 1977; 296:769-74 17 Heflin AC, Brigham KL. Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia. J Clin Invest 1981; 68:1253-60 18 Flick MR, Perel A, Staub NC. Leukocytes are required for increased lung microvascular permeability after microembolization in sheep. Circ Res 1981; 48:344-51 19 Flick M, Perel A, Staub N. Increased lung vascular permeability after microemboli in unanesthetized sheep requires circulating leukocytes. Physiologist 1979; 22:39-48 20 Tahamont M~ Malik AB. Granulocytes mediate the increase in pulmonary vascular permeability after thrombin embolism. J Appl Physiol Respir Environ Exercise Physioll983; 54:1489-95 21 Fox R, Hoidal J, Brown D, Repine J. Pulmonary inflammation due to oxygen toxicity, involvement of chemotactic factors and polymorphonuclear leukocytes. Am Rev Respir Dis 1981; 123:521-23 22 Guenter CA. Role of leukocytes in the lung after endotoxin administration. Adv Exp Med BioI 1971; 23:2285 23 Millen JE, Glauser FL, Smeltzer D, Egan ~ Propst K, Fischer ~ et ale The role ofleukocytes in ethchlorvynol-induced pulmonary edema. Chest 1978; 73:75-8 24 MacGlashan DW, Schleimer R~ Peters S~ Schulman EE, Adams GK, Newball HH, et aI. Generation of leukotrienes by purified human lung mast cells. J Clin Invest 1982; 70:741-51 25 Spagnuolo PJ, Ellner JJ, Hassid A, Dunn MJ. Thromboxane A2 mediates augmented polymorphonuclear leukocyte adhesiveness. J Clin Invest 1980; 66:406-14 26 Serneri GGN, Abbate R, Gensini G~ Panetta A, Casolo GO, Carini M. TxAt production by human arteries and veins. Prostaglandins 1983; 25:753-63 27 Aharony D, Silver M], Smith JB, Nissenbaum M, Sedar AW, Macerak E. Prostaglandin 12 and thromboxane ~ can be produced by endothelial cells in situ and in culture. Fed Proc 1980; 39:391 28 Utsunomiya l: Krauz MM, Dunham, B, Valeri CR, Levine L, Shepro D, et ale Modification of the inflammatory response to aspiration with ibuprofen. Am J Physiol 1982; 243:H903-10 29 McGuire ww, Spragg RG, Cohen AB, Cochrane CG. Studies in the pathogenesis of the adult respiratory distress syndrome. J Clin Invest 1982; 69:543-53 30 TIllGO, Johnson KJ, Kunbel R, Ward PA. Intravascular activation of complement and acute lung injury: dependency on neutrophils and toxic oxygen metabolites. J Clin Invest 1982; 69:1126-35 31 Taylor GW, Morris HR. Lipoxygenase pathways. Br Med Bull 1983; 39:219-22 32 Dunham BM, Hechtman HB, ValeriCR, Shepro D. Antiinflammatory agents inhibit hamster microvascular permeability induced by stimulated human polymorphonuclear leukocytes. Microcirculation: Endothelium and Inflammation (to be published) 33 Watkins WD, Huttemeier PC, Kong D, Peterson MB. Thromboxane and pulmonary hypertension following E coli endotoxin infusion in sheep: effect of imidazole derivative. Prostaglandins 1982; 23:273-85 CHEST / 86 / 4 / OCTOBER, 1984

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