Heterogeneity of airway inflammation in persistent asthma : evidence of neutrophilic inflammation and increased sputum interleukin-8.

Although salutary effects of female sex steroids have been demonstrated not only in proestrus females but also in male animals treated with estradiol in different models of trauma, it remains unknown whether sex hormones influence post-traumatic immune response in humans. We therefore investigated the effect of sex and age on organ dysfunction and clinical course in patients with multiple injuries. Polytraumatized patients (injury severity score>16) between 16 and 65 years old admitted to the Hannover Medical School Level 1 trauma center between January 1997 and December 2001 were included. Marshall Score for multiple organ dysfunction syndrome (MODS) was calculated for at least 14 days. The length of stay in intensive care unit and the ventilator days were recorded in addition to the number of transfusions the patient received. A total of 106 males and 37 females were included in the study. Patients with MODS had increased plasma levels of IL-6, IL-8, and IL-10. Furthermore, patients with organ dysfunction had more frequent sepsis and higher mortality rates. In addition, MODS was associated with extended length of stay in the intensive care unit and increased ventilator days. Females not older than 50 years with an injury severity score greater than 25 suffered significantly less MODS and sepsis compared with age-matched males. Moreover, they had significantly lower plasma cytokines. Thus, in this prospective study, sex difference was confirmed in MODS and sepsis, with a benefit observed in females. Although the levels of sex steroids were not measured, it seems that the protective effects may be due to estrogen effects on plasma cytokines. This suggestion is based on the fact that such salutary effects were apparent predominantly in premenopausal females.

Influence of sex and age on mods and cytokines after multiple injuries.

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.

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Pharmacotherapy of acute lung injury and acute respiratory distress syndrome.

To test whether pulmonary and extrapulmonary acute lung injury (ALI) of identical mechanical compromise would express diverse morphological patterns and immunological pathways. For this purpose, a ...

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.01182.2004

Pulmonary and extrapulmonary acute lung injury: inflammatory and ultrastructural analyses.

Regulation of the neutrophil life span by apoptosis provides a fine balance between their function as effector cells of host defense and a safe turnover of these potentially harmful cells. Alterations of neutrophil apoptosis are associated with a number of diseases. As do other cell types, neutrophils possess components of both extrinsic and intrinsic apoptotic routes. The intrinsic pathway of apoptosis seems to be of major importance in neutrophils since they are programmed for a rapid spontaneous cell death. However, in neutrophils this mechanism of apoptosis has special features, probably due to peculiarities of neutrophil mitochondria, which are believed to be a core regulator of intrinsic cell death. A better understanding of mechanisms underlying neutrophil cell death would help to understand neutrophil physiology and contribute to the search of new approaches for handling of pathology related to disturbances in neutrophil apoptosis and also increase our knowledge of inflammation in general.

Apoptosis of Neutrophils

Objective To evaluate the role of interleukin 8 (IL-8) in the regulation of neutrophil (PMN) apoptosis in normal plasma and plasma from patients with early, fulminant acute respiratory distress syndrome (ARDS). Design Experimental study using cultured human PMNs. Setting University hospital, level I trauma center. Participants Plasma was obtained from 6 patients with early, fulminant posttraumatic ARDS (mean Injury Severity Score, 26). All samples were drawn within 24 hours after injury. Plasma was also taken from 13 healthy control subjects. These controls were also used as sources of PMNs. Main Outcome Measures Effect of early, fulminant ARDS and normal plasma on spontaneous apoptosis, CD16, and CD11-b expression in PMNs in vitro; levels of IL-8 in plasma; correlation of extracellular IL-8 concentration with rate of PMN apoptosis; and effect of IL-8 blockade on PMN apoptosis, CD16, and CD11-b expression in ARDS and normal plasma. Results Plasma from patients with early, fulminant ARDS inhibited spontaneous PMN apoptosis at 24 hours (35%±5% vs 54%±5%; P =.01). Neither CD16 nor CD11-b differed significantly between the 2 groups. The mean plasma level of IL-8 in patients with early, fulminant ARDS was 359±161 pg/mL vs 3.0±0.4 pg/mL in healthy controls ( P P P =.008) but not in plasma from patients with early, fulminant ARDS (29%±5% with monoclonal antibody vs 34%±6% without monoclonal antibody; P =.67). It had no effect on CD16 or CD11-b expression in either plasma. Conclusions Plasma from patients with early, fulminant ARDS contains soluble factors that inhibit PMN apoptosis in vitro. Low levels of IL-8 inhibit PMN apoptosis in normal plasma. Although plasma levels of IL-8 are markedly elevated in early, fulminant ARDS, IL-8 is not directly responsible for the antiapoptotic effect of plasma from patients with early, fulminant ARDS.

/pdf/role-of-interleukin-8-in-the-genesis-of-acute-respiratory-xrhcqp05sf.pdf

Andrea M. Fusco

Papers

Role of Interleukin 8 in the Genesis of Acute Respiratory Distress Syndrome Through an Effect on Neutrophil Apoptosis