Subpopulation of Hyperresponsive Polymorphonuclear Neutrophils in Patients with Adult Respiratory Distress Syndrome: Role of Cytokine Production

Abstract

To gain further insight into the pathogenesis of the adult respiratory distress syndrome (ARDS), we studied possible relationships among the activation status of circulating polymorphonuclear neutrophils (PMN), cytokine levels, and the severity of lung injury in 31 patients: 15 with ARDS, nine with severe pneumonia uncomplicated by ARDS, and seven mechanically ventilated with neither ARDS nor pneumonia. Nine healthy subjects served as controls. Using flow cytometry, we identified a subpopulation of PMN with an increased capacity to generate hydrogen peroxide after stimulation ex vivo in all three patient groups; significantly higher values were found in those with ARDS. The PMN stimulation index, a reflection of the degree of hyperresponsiveness, correlated with elevated levels of tumor necrosis factor-alpha (TNF alpha) in plasma, and both spontaneous and lipopolysaccharide-induced TNF alpha production by cultured monocytes. These biologic expressions of PMN activation and cytokine generation both correlated with indices of the severity of lung injury, but not with the overall clinical severity. In contrast, IL-6 and IL-1 beta showed little or no relationship with either the degree of lung injury or PMN hyperresponsiveness. We conclude that TNF-alpha-primed PMN may play a major role in the pathogenesis of ARDS-associated lung injury.

Oncostatin M Production by Blood and Alveolar Neutrophils during Acute Lung Injury

“…In a mouse model, OSM administration inhibited lipopolysaccharide-induced TNF␣ production and increased IL-6 production, but did not affect IL-10 and IL-1␤ levels (Wallace et al, 1999). These in vivo findings are in keeping with the low TNF␣, IL-10, and IL-1␤ levels and the high IL-6 levels that we have found previously in BAL fluid from patients with ALI (Chollet- Martin et al, 1992Martin et al, , 1994Martin et al, , 1996, and suggest that OSM produced by alveolar PMN could modulate local production of these cytokines.…”

“…In our patients, the normal plasma OSM levels and the OSM production by blood PMN ex vivo suggest that OSM is not involved in alveolar PMN recruitment. However, in the lung, OSM produced locally by PMN could act as an autocrine or paracrine proinflammatory mediator; indeed, OSM can trigger the release of phospholipase A2 in vitro (Haselmann and Goppelt-Struebe, 1997) and can induce the secretion of gp91phox protein, one of the NADPH oxidase components involved in ROS hyperproduction by PMN in patients with ALI (Chollet-Martin et al, 1992;Hoidal et al, 1998).…”

“…Interest in the pathogenetic mechanisms of ALI has focused in recent years on interactions between PMN and cytokines (Pittet et al, 1997). In particular, several reports from our group and others have indicated that circulating and alveolar PMN are activated and that proinflammatory cytokines may play an active role in this process (Chollet-Martin et al, 1992Martin et al, 1991). Activated PMN can damage the lung through several potential mechanisms, including the release of proteases, cytokines, and reactive oxygen species (ROS), but recent data also suggest a role for PMN in the modulation of inflammation and tissue repair (Boutten et al, 1998;Donnelly et al, 1995).…”

Ventilator-Associated Pneumonia: Diagnosis, Treatment, and Prevention

“…The poor accuracy of clinical criteria for diagnosing VAP should not be surprising considering that purulent tracheobronchial secretions are invariably present in patients receiving prolonged mechanical ventilation and are seldom caused by pneumonia. In addition, the systemic signs of pneumonia such as fever, tachycardia, and leukocytosis are nonspecific; they can be caused by any state that releases the cytokines interleukin-1, interleukin-6, tumor necrosis factor alpha, and gamma interferon (33,34,63,135). Examples of such conditions include trauma, surgery, the fibroproliferative phase of ARDS, deep vein thrombosis, pulmonary embolism, and pulmonary infarction.…”

Flow cytometric investigation of neutrophil oxidative burst and apoptosis in physiological and pathological situations

“…The degree of hyperresponsiveness correlated with the lung injury score and elevated levels of TNF and IL-8 in both plasma and monocyte culture supernatants. The presence of this subpopulation may, therefore, contribute to the neutrophil-mediated process in the pathogenesis of ARDS (27).…”