Table 1.

Evidence for and against PMN involvement in ARDS, based on both animal models as well as human data

Evidence for PMN involvement in ARDS	Evidence against PMN involvement in ARDS
A) Histopathological PMN evidence from ARDS patients: 1) Pathologic finding in lungs of 9 ARDS patients included interstitial and alveolar edema with accumulation of alveolar PMNs, macrophages and erythrocytes[75] 2) Case report of 1 ARDS patient who demonstrated microvascular granulocyte aggregation and lung edema upon lung histological analysis [76] 3) Pathological finding based on 59 ARDS patients showed diffuse alveolar damage with PMNs, macrophages, erythrocytes, hyaline membranes and protein-rich edema fluid in the alveolar spaces [77]	A) Occurrence of ARDS in neutropenic patients: 1) 11 neutropenic patients with ARDS, without pulmonary PMN filtration [78] 2) 4 neutropenic with ARDS [79] 3) Development of ARDS in 22 children with neutropenia, no signs of pulmonary PMN infiltration [80] 4) ARDS development in 5 neutropenic patients after bone marrow transplantation for chronic myeloid leukemia [81] 5) 17 neutropenic patients with septic ARDS, deactivation of alveolar macrophages is suggested in these patients [82] 6) 12 neutropenic cancer patients with septic-related ARDS, deactivation of monocytes is suggested in these patients [83] 7) 7 episodes of ARDS occurring in leukemic patients with longstanding (average 11 days) and severe neutropenia [84] 8) 5 neutropenic patients with ARDS [85] 9) Histologic examination of the lungs from two neutropenic patients with ARDS demonstrated the absence of PMNs [86]
B) ARDS patient (-derived) PMN data: 1) Natural inhibitor of PMN function correlates with decreased PMN mediated ARDS [87] 2) Retention of ex-vivo primed PMNs in ARDS patients [88] 3) Lung PMNs in ARDS correlate with abnormalities of gas exchange and lung protein permeability, and neutrophil products capable of mediating lung injury can be recovered from the lungs of these patients [89] 4) Increased levels of lactoferrin, a specific granule protein of PMNs, in ARDS patients, also in relation to circulating PMN numbers [90] 5) High concentration of peptide released by macrophages caused PMN to secrete azurophilic granule enzymes in ARDS patients [91] 6) Increased pulmonary levels of PMN-derived S100A12 in patients with ARDS [92] 7) Increased expression of PMN-related genes in patients with early sepsis-induced ARDS [93] 8) Increased PMN-ROS activation in post-traumatic ARDS patients [94] 9) Alteration of chemotactic and secretory processes in PMNs derived from ARDS patients [95] 10) Granulocyte adherence in pulmonary and systemic arterial blood samples from ARDS patients [96] 11) Increased IL-8-related PMN elastase complexes correlate to severity in mechanically ventilated and large sepsis-related ARDS patients [97] 12) Lower ADCC and bacterial killing ability of peripheral blood and alveolar PMNs from ARDS patients [98] 13) Increased PMN elastase activity in alveolar fluid from ARDS patients [99] 14) Ex-vivo stimulation of PMNs from ARDS patient demonstrate hyperresponsiveness and correlate with elevated plasma levels of TNF-α [100] 15) Low proportion of apoptotic PMNs in BAL of ARDS patients [101] 16) Inhibition of PMN apoptosis by BAL fluid from patients on days 1 and 3 of ARDS (not at later stages) [102] 17) Lower peripheral blood-derived PMN apoptosis in sepsis-induced ARDS [103] 18) PMNs from ARDS patients demonstrate a varying degree of activation [104] 19) Abnormal PMN-lung interaction in ARDS patients as observed by increased pulmonary PMN localization in ARDS using scintigraphy [105] 20) Increased ROS-releasing and metabolic activity of PMNs derived from ARDS patients [106] 21) Impaired function of lung and blood PMNs of ARDS patients (impaired superoxide anion and hydrogen peroxide production and impaired microbicidal activity of lung PMNs and reduced migration of alveolar PMNs) [107] 22) IPulmonary PMN accumulation (111In-labeled PMNs) in 3 sepsis-related ARDS patients [108] 23) IPMN elastase-releasing factors described in BAL from ARDS patients [109] 24) Reduced bactericidal activity (impaired phagocytosis and killing) of blood PMNs from ARDS patients [110] 25) NETs were observed in bronchial aspirates from gastric-aspiration-induced ARDS patients [111] 26) Presence of NETs in human patients with pneumonia and sepsis-related ARDS. Increased plasma NETs were associated with ARDS severity and mortality, and lower plasma DNase I levels were associated with the onset of sepsis-induced ARDS [112] 27) G-CSF and IL-8 but not GM-CSF correlate with severity of increased pulmonary PMNs in BAL fluid from ARDS patients [113] 28) Increased presence of PMNs in BALs from sepsis and trauma-related ARDS patients [114] 29) Increased blood PMN-elastase levels in ARDS patients [115] 30) Leukocyte and PMN-derived microparticles were found to be elevated in BALs from ARDS patients [116] 31) Increased numbers of PMNs in BALs from ARDS patients, with PMNs displaying adherence-promoting activity [117] 32) High levels of PMNs in BALs from patients with early ARDS [118]	B) ARDS patient (-derived) PMN data: 1) In clinical trials patients with severe pneumonia received granulocyte colony-stimulating factor (Filgrastim), which increased the number of circulating PMNs 3-fold, but this did not increase the incidence or severity of lung injury [119] 2) Massive oxidative stress observed through plasma analysis from ARDS patients, however, ROS generation from PMNs was found be normal on day 0 and decreased to day 6 in ARDS patients [120]
C) Pulmonary PMN infiltration in animal models of ARDS: 1) Endotoxemia rabbit ARDS model [121] 2) Lung lavage rat ARDS model [122] 3) Malaria-ARDS mouse model [123] 4) Endotoxemia pig model, with protection by PMN depletion [124] 5) H9N2 virus induced murine ARDS model [125] 6) Acid-aspiration induced rat ARDS model [126] 7) Murine lipopolysaccharide-induced endotoxemia model [127] 8) Sepsis-induced primate ARDS model [128]	C) PMN data from ARDS animal models: 1) Occurrence of ARDS in leukopenic (granulocyte-depleted) mini pigs undergoing elastase-mediated ARDS [129]
D) Increased PMN responses in animal models of ARDS: 1) Increased ROS production in rat endotoxemia ARDS model [130] 2) Evidence for PMN-ROS activity in rat model of IL-1-instilled ARDS [131] 3) NETs contribute to murine acid-aspiration-induced ARDS [111] 4) Excessive PMNs and pulmonary NET formation in a murine model of influenza-induced ARDS [132]