Pathogenesis Of ARDS Research Articles

An Appreciation of Functional Role of Macrophage in the Acute Lung Injury in the Neutropenic Rat

BACKGROUND: It has long been suggested that neutrophils and their products are implicated as the central mediators of the acute lung injuries. Contrary to the dominant role of neutrophils in ARDS, many cases of ARDS has occurred in the setting of severe neutropenia without pufrnonary neutrophil infiltration. Therefore it is certain that effector cell(s) other than neutrophil play an important role in the pathogenesis of ARDS. This experiment was performed to define the mechanism of ARDS in the setting of neutiopenia, 1) by comparing the severity of endotoxin-induced lung injury, 2) by measurement of hydrogen peroxide production and cytokine concentration in the bronchoalveolar lavage cells and fluids obtained from different rats with and without cyclophosphamide-pretreatment. METHOD: The male Sprague-Dawleys were divided into the normal control (NC)-, endotoxin (ETX)-, and cyclophosphamide (CPA)-group in which neutropenia was induced by injecting cyclophosphamide intraperitoneally. Acute lung injury was evoked by injecting lipopolysaccharide (LPS) into a tail vein. The bronchoalveolar lavage (BAL) was performed at 3 and 6 hour after administration of LPS to measure the change of cell counts and concentrations of protein and cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Hydrogen peroxide (HPO) production from BAL cel]s was measured at 6 hour after LPS administration by phenol red microassay with and without zymosan stimulation. RESULTS: The results were as follows. A change of leukocyte counts in the peripheral blood after treatment with CPA More than 95% of total leukocytes and neutrophils were reduced after CPA administration, resulting in severe neutropenia. A change of BAL cells In the ETX-group, the number of total cells (p<0.01) and of macrophage and neutrophll (p<0.05) were increased at 3 and 6 hour after LPS administration compared to those of NC- group. In the CPA-group, the number of total leukocyte and macrophage were not changed after LPS administration, but neutrophil counts were significantly reduced and jt took part in less than 0.1% of total BAL cells (p<0.01 vs NC-group). BAL cells in this group were almost all macrophages (99.7%). A change of protein concentration in the BALF In the ETX-group, protein concentration was increased at 3 hour and was more increased at 6 hour after LPS administration (p<0.05 and <0.01 vs NC-group, respectively). In the CPA-group, it was also significantly elevated at 3 hour after LPS administration (p<0.05 vs NC-group) , but the value was statistically not different from that of ETh-group. The value measured at 6 hour after LPS administration in the CPA-group became lower than that of ETX-group (p<0.05), but showed still a higher value compared to that of NC-group (p<0.05). A change of cytokine concentration in the BALF TNF-alpha and IL-6 were elevated in the ETX- and CPA-group compared to those of NC-group at both time intervals. There was no statistical difference in the values of both cytokines between the ETX- and CPA-groups. Measurement of hydrogen peroxide production from BAL cells There was no intergroup difference of HPO production from resting cells. HPO production after incubation with opsonized zymosan was significantly elevated in all groups. The percent increment of HPO production was highest in the ETX-group (89.0%, p<0.0008 vs NC-group ), and was 42.85 in the CPA-group (p = 0.003 vs NC-group ). Conclusion Acute lung injury in the setting of neutropenia might be caused by functional activation of resident alveola r macrophages.

The Interdependence of Lung Antioxidants and Antiprotease Defense in ARDS

As in hereditary alpha 1-antitrypsin deficiency, protease-antiprotease and oxidant-antioxidant balances play a significant role in the pathogenesis of ARDS. However, the disease processes and possibilities for therapeutic intervention differ markedly.

Priming of Phospholipases A2 of Human Neutrophils by Tumor Necrosis Factor

Tumor necrosis factor primes polymorphonucleotides (PMN) for receptor mediated stimulation (eg, by C5a or fMLP), which might contribute to the pathogenesis of ARDS. We previously reported that primed PMN, stimulated with fMLP, have increased release of free arachidonic acid (AA) and eicosanoids (5-HETE, LTB4) using PMN-labelled for 30 min with 3H-AA (which labels primarily PC and PI phospholipids). Thus, primed PMN could provide a source of the AA and LTB4 which occurs during ARDS. Many aspects of such events remain uncertain, including the mass of AA released by such cells and the specific phospholipase A2 involved.

Immunologic Therapy for ARDS, Septic Shock, and Multiple-Organ Failure

Advances in cytokine biology and molecular biology have led to the development of novel immunologic approaches to the treatment of septic shock, ARDS, and MOF. These advances are necessary since improvements in supportive care clearly fall short of the hoped-for reductions in mortality associated with these disorders. As noted in this review, these new therapies are directed at three distinct levels of the inflammatory cascade: (1) the inciting event or insult (eg, endotoxin); (2) the mediators (eg, TNF, IL-1); and (3) the effector cells (eg, neutrophils). The current status of these treatments has been reviewed; and while each individual therapy has shown potential, it is likely that combinations of these agents may be necessary to substantially impact on survival. That is, due to the complexity and redundancy of the inflammatory network, it is doubtful that a "magic bullet" will be found. However, it is also clear that advances in our understanding of the pathogenesis of ARDS, septic shock, and MOF at the molecular level have provided clinicians with powerful weapons with which to do battle. It remains to be seen which ones will work the best.

The cytokine network in the critically ill.

There is increasing experimental and clinical evidence that a number of cytokines play a major role in the response to injury and infection and in the development of organ damage in critically ill patients. Tumour necrosis factor (TNF) is now proposed to be a key mediator of organ injury during sepsis. It is elevated early in the course of septic shock and high levels correlate with unfavourable outcome. In animals it can produce the effects of endotoxin. The prophylactic administration of anti-TNF antisera protects mice and rabbits from lethal effects of lipopolysaccharide. Interleukin-1 (IL-1) is an endogenous pyrogen which induces leukocytosis and muscle catabolism. It causes hypotension and tachycardia by reducing smooth muscle contractility. IL-1 receptor blockers have been shown to diminish mortality in experimental endotoxic shock. Interleukin-6 (IL-6) is a pyrogen and lymphocyte activator. It is the major stimulus to acute phase protein production by the liver. A recently described neutrophil-activating peptide (Interleukin-8; IL-8) may be involved in the pathogenesis of ARDS. High blood levels of IL-8 have been found in patients with septic shock. Platelet-derived growth factor (PDGF) has been shown to stimulate TNF production, leukocyte chemotaxis and pulmonary vasoconstriction in response to endotoxin. Other cytokines and growth factors have not yet been studied in critical illness. The cytokine network can be either protective or damaging. Its activation during critical illness triggers complex and still poorly understood interactions. A better comprehension of its role in protection from infection and in the pathogenesis of multiple organ failure may allow therapeutic manipulations aimed at minimising adverse effects while retaining immunological protection.

Current Understanding of the Pathogenesis of Gram-negative Shock

There is increasing evidence that gram-negative bacteria via endotoxin induce the excessive production of inflammatory cytokines, which are active in the pathogenesis of septic shock, multiorgan failure, and ARDS. In animals the injection of TNF induces pathophysiologic and histopathologic changes that are characteristic of the septic shock syndrome, and in patients there is a close association between levels of TNF and the severity of the shock. IL-1 and IFN-gamma markedly potentiate the toxic TNF effects in animal experiments. IL-6 is frequently released into serum during septic shock, and its levels are associated with the severity of the shock. The cytokine is probably not directly involved in the pathogenesis of the shock but may contribute to fever, neutrophilia, and production of acute-phase proteins. Endothelial cells and neutrophils are important target cells for the cytokines in mediation of septic shock and late complications. Underlying conditions like cancer, trauma, burns, and other kinds of stress may alter the induction mechanism of the cytokines and the susceptibility of the organism. The pathogenetic significance of TNF and other cytokines in different categories of septic shock remains to be clarified.

Actions and interactions of mediator systems and mediators in the pathogenesis of ARDS and multiorgan failure

A great variety of mediators and mediator systems are involved in the disturbance of the microcirculation and vascular permeability following polytrauma and sepsis. The locally accentuated, organ related activation and the cooperation of several of these mediators and mediator systems over a longer period of time seem to be responsible for the development of an acute organ failure in terms of ARDS and MOF. Cytokines from macrophages seem to be the determining factors converting a primarily functional and reversible systemic vascular reaction into organ related morphological lesions. This pathogenetic complexity has to be considered in future concepts for therapy and prophylaxis with regard to the hierarchical rank of the mediators involved.

Pulmonary Pathology of the Adult Respiratory Distress Syndrome

Lung morphology in ARDS reflects the rapid evolution from interstitial and alveolar edema to end-stage fibrosis consequent to injury of the alveolocapillary unit. This morphologic progression, termed diffuse alveolar damage, has been subdivided into sequentially occurring exudative, proliferative, and fibrotic phases. Pulmonary lesions correlate with the phase of alveolar damage rather than with its specific cause. As suggested by experimental models of acute lung injury, the pathologic features seen in humans are consistent with the effects of a host of injurious stimuli and the complex interaction of inflammatory mediators on alveolar epithelial and capillary endothelial cells. Although ARDS frequently culminates in "interstitial" fibrosis, the organization of intraluminal exudate dominates the histologic picture in the proliferative phase and establishes the framework for subsequent fibrous remodeling of the lung. Involvement of the pulmonary vasculature is an important aspect of ARDS, from the initial phase of edema to the terminal stage of intractable pulmonary hypertension. Vascular lesions include thrombotic, fibroproliferative, and obliterative changes, which, like the parenchymal lesions, correlate with the temporal phase of diffuse alveolar damage. Although ARDS is characterized by extensive bilateral lung involvement, alveolar damage can affect the lung in a localized fashion. "Regional alveolar damage" is associated with the same clinical risk factors as diffuse damage, suggesting that there is a spectrum in the extent of lung involvement and disease severity in patients at risk for ARDS. The factors that govern which patients will develop the fulminant syndrome are poorly understood. It must be re-emphasized that the lung is stereotyped in its response to injury, and, consequently, descriptive, or even quantitative, studies of lung morphology can only provide clues regarding the initiating factors and pathogenetic mechanisms of ARDS. Progress in understanding the pathogenesis of ARDS and the devising of rational approaches to therapy will ultimately depend on careful clinical and experimental studies that unravel basic mechanisms of cellular injury and response. The course of these investigations must be guided by and constantly correlated with the pathologic features that occur in humans.

Adult respiratory distress syndrome

The relationship between leukotriene C4 (LTC4), platelet activating factor (PAF), and adult respiratory distress syndrome (ARDS) was studied in nine patients and 84 control subjects. A leukocyte adherence inhibition (LAI) assay induced by each of the ligands was used to monitor the subjects for 3 consecutive days or until clinical recovery was noted. LAI was considered to be positive if the nonadherence index (NAI) was greater than 30 for LTC4 or greater than 20 for PAF. LAI was negative in all healthy subjects using both ligands. LTC4-induced LAI was positive in all nine ARDS patients and reverted to negative after recovery from the syndrome, while three (33.3%) of nine patients responded to PAF. In contrast, of the 84 control subjects, LAI was induced by LTC4 in only three (3.3%) and by PAF in five (5.9%). The mean NAI (52.2 +/- 18) of LTC4-induced LAI in ARDS patients was significantly (p less than .05) higher when compared with the control group (-5 +/- 6.4), whereas that of PAF-induced LAI was less than 20 in both groups, indicating that LTC4 is a more specific ligand than PAF. All three patients in whom ARDS was caused by sepsis responded to both LTC4 and PAF, but results of specific receptor-antagonist experiments indicated that each compound acted independently. The mean NAI for LTC4 (58.5 +/- 10) and PAF (49.1 +/- 12) in patients with septic ARDS were significantly (p less than .05) higher when compared with those of patients with sepsis alone (0.5 +/- 9.9 and 4.4 +/- 17, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The Effects of Heterologous Platelet Transfusion on Pulmonary Function during ARDS

Pulmonary platelet sequestration has been implicated in the pathophysiology of ARDS. Since HPTs are frequently given therapeutically to patients with ARDS, a serious concern clinically has been the possibility that platelet transfusions might worsen pulmonary function in such patients. To prospectively evaluate this issue, we assessed the effects of HPT on two parameters of pulmonary function: (1) Qs/Qt; and (2) PVR. Measurements were made immediately before and at 1 hour and 4 hours after HPT in 16 patients during 18 separate episodes of ARDS and in 11 control patients. The ARDS had been present for at least 48 hours in all patients at the time of study. Prior to HPT, patients with ARDS had significantly worse pulmonary function compared to control subjects. Although a small number of patients with ARDS had large changes in PVR and Qs/Qt after HPT, no group showed significant changes in any pulmonary parameter following transfusion. Neither individual changes in the platelet count after HPT nor the duration of ARDS before HPT was associated with changes in pulmonary function after platelet administration. We concluded that therapeutically required HPT did not significantly worsen pulmonary function at up to four hours after transfusion in this group of patients with well-defined and fully evolved (greater than 48-hour duration) ARDS. The reason for this absence of effect was not known, but the pathogenesis of ARDS might only be susceptible to alteration during the early developmental stage.

Kinetics of leukocyte sequestration in the lungs of acutely septic primates: A study using 111In-labeled autologous leukocytes

To further clarify the role of leukocytes in the pathogenesis of ARDS, we studied the localization and kinetics of leukocyte migration using 111In-labeled autologous white cell scans ( 111In wbc scans) in four primates made acutely septic with infusions of Escherichia coli. Whole body images were obtained with a gamma camera and were acquired on computer every 15 min beginning immediately after the E. coli infusion. Simultaneous measurements of C5a and peripheral blood leukocyte count were also obtained. Within 5 min of initiating sepsis, three major events occurred: complement activation as measured by the production of C5a, a profound fall in peripheral leukocyte count, and a significant increase in the sequestration of leukocytes in the lungs. The pulmonary sequestration reached a peak at 15 min with a mean of 152% of baseline activity. This sequestration consisted of a population that was predominantly neutrophils. Damage to the pulmonary capillary endothelium was demonstrated by an increase in extravascular lung water. The results support a role for neutrophils and complement as mediators in the pathogenesis of ARDS.

Immune Dysfunction in the Critically Ill Infant and Child

Factors contributing to the high prevalence of immunodeficiency in the PICU population include conditions that lead to frequent requirement of intensive care, suppression of immunity secondary to an acute insult, and iatrogenic measures. The immunodeficiency observed in the critically ill correlates well with their susceptibility to infection and explains the high prevalence of nosocomial sepsis in the PICU--a major cause of morbidity and mortality in critically ill children. Dysactivation of the immune system during an acute insult, with the subsequent release of humoral mediators from activated immune cells, leads to tissue injury and may be involved in the pathogenesis of ARDS, DIC, capillary leak syndrome, and to the development of multiple organ system failure. Suggested approaches to correct the immunodeficiency in the critically ill include reconstitutional immunotherapy, mediator-inhibiting drugs, and mediator removal by plasma exchange. Intensivists should be aware of the phenomenon of immunodeficiency in the critically ill, be accordingly aggressive in diagnosing and treating infections, and avoid, as much as possible, measures that further suppress immunity.

ARDS: refinement of concept and redefinition.

AMERICAN REVIEW OF RESPIRATORY DISEASE who wrote Adult Respiratory Distress Syndrome (May it Rest in Peace) (2). In the interim, we have each continued both clinical and basic research designed to unravel some of the many remaining mysteries about the pathogenesis of ARDS and factors associated with the prognosis. Gradually, a fairly standard approach to supportive therapy has emerged that involves mechanical ventilation, use of positive end expiratory pressure (PEEP), blood and fluid replacement, treatment ofpresumed or identified infections, and nutritional and psychological support. Still today more than 50070 ofpatients die ofARDS in either the early or late stages of disease. Also this interval has seen the definition of many of the risk factors associated with ARDS (3, 4) and the factors associated with prognosis once ARDS is established (5). On the bright side is the favorable outcome of patients who can be weaned from mechanical ventilation and can leave the hospital (6). Those investigators who have continued to observe their patients over many years have marvelled at the potential of the lung to remodel itself and reestablish good or even normal ventilatory and gas transfer function of the lung. Many patients have minimal or no symptoms at all in the late recovery phase. The expanded definition of the adult respiratorydistress syndrome proposed by John Murray and associates in this issue has considerable merit in my opinion (7). Wecertainly need a grading system for severity of lung injury. Stratifying patients by the degree of impaired oxygenation along with PEEP requirements is both reasonable and practical. It will be potentially useful to identify causal factors related to the initiation of this syndrome. I am personally delighted at the suggestion that ARDS not be defined in terms of measurements made by a flow-directed catheter. After all, the flow-directed catheter didn't even exist when we offered our three early papers on ARDS (8-10). Certainly hemodynamic measurements will play a strategic role in selected patients as a guide to therapy and for clinical research purposes in certain patients with informed consent. I believe stratification by bedside measurements of overall compliance is also reasonable and practical. These measurements will be available and can be made serially in all patients requiring mechanical ventila-

Pancreatitis-induced acute lung injury. An ARDS model.

Cerulein-induced acute pancreatitis in rats is associated with acute lung injury characterized by increased pulmonary microvascular permeability, increased wet lung weights, and histologic features of alveolar capillary endothelial cell and pulmonary parenchymal injury. The alveolar capillary permeability index is increased 1.8-fold after a 3-hour injury (0.30 to 0.54, p less than 0.05). Gravimetric analysis shows a similar 1.5-fold increase in wet lung weights at 3 hours (0.35% vs. 0.51% of total body weight, p less than 0.05). Histologic features assessed by quantitative morphometric analysis include significant intra-alveolar hemorrhage (0.57 +/- 0.08 vs. 0.12 +/- 0.02 RBC/alveolus at 6 hours, p less than 0.001); endothelial cell disruption (28.11% vs. 4.3%, p less than 0.001); and marked, early neutrophil infiltration (7.45 +/- 0.53 vs. 0.83 +/- 0.18 PMN/hpf at 3 hours, p less than 0.001). The cerulein peptide itself, a cholecystokinin (CCK) analog, is naturally occurring and is not toxic and in several in vitro settings including exposure to pulmonary artery endothelial cells, Type II epithelial cells, and an ex vivo perfused lung preparation. The occurrence of this ARDS-like acute lung injury with acute pancreatitis provides an excellent experimental model to investigate mechanisms and mediators involved in the pathogenesis of ARDS.

Bronchoalveolar Lavage in Patients with the Adult Respiratory Distress Syndrome

BAL in patients with ARDS provides material containing the soluble and cellular constituents of the alveolar compartment, and hence is a useful tool for the study of the pathogenesis of ARDS. The technique is imperfect as it is prone to problems of data acquisition and interpretation. However, it is lung-specific and may be used in serial studies of patients over the course of their disease. A large amount of evidence is rapidly being accumulated which documents the presence of effectors of inflammation in the BAL fluids of patients with ARDS. Confirmation of the importance of such mediators, pathways, or cellular constituents of BAL fluid in establishing the pathogenesis of ARDS ultimately depends upon proof of the efficacy of specific clinical interventions which both arrest the activity of the effector and predictably alter the course of the disease.

Adult respiratory distress syndrome

We reviewed the hospital charges, underlying diagnoses, and hospital outcomes in 39 patients with adult respiratory distress syndrome (ARDS) admitted to the respiratory ICU of a university hospital between July 1979 and June 1981. Charges per patient ranged from $9263 to $187,893 with a median of $52,894. Median ICU charges were $2430/day. Only 7 patients survived their hospitalization. Compared to nonsurvivors, survivors had longer ICU and hospital stays but lower daily ICU charges ($1683 vs. $2760,p = .001). Only 1 of 27 patients with underlying hematologic/oncologic diseases survived, compared to 6 of 12 patients with other underlying diseases. Charges and outcomes in this study reflect the underlying patient population and philosophy of care at the study institution. Considering the high costs and poor outcomes in ARDS patients with underlying hematologic/oncologic problems, we recommend that the appropriateness of aggressive treatment be reconsidered.