Search PubMed⌕ Search

Biomedical subjects

C Haslett

Publications and source records attributed to C Haslett.

At least 37 records · Page 2Linked to original sources
PubMed2001

Elevated levels of interleukin-8 in donor lungs is associated with early graft failure after lung transplantation.

Increased levels of the neutrophil chemokine interleukin (IL)-8 in the lungs of severe trauma patients can predict subsequent development of acute respiratory distress syndrome. Because the lungs of brain-dead organ donors can contain high levels of IL-8, we hypothesized that this may predispose to early graft failure in the recipient after lung transplantation. Twenty-six organ donors prospectively satisfying clinical criteria for lung donation underwent bronchoalveolar lavage and lung biopsy to determine the effect of neutrophil infiltration and IL-8 expression in the donor lung on graft function and survival in 26 respective recipients after lung transplantation. Nine recipients developed severe graft dysfunction, of whom six subsequently died (median survival: 24 d [range: 5 to 39 d]); all others survived beyond 6 mo. The IL-8 signal in the donor lung correlated with the percent neutrophils in bronchoalveolar lavage fluid (BALF) before implantation (42.4 +/- 7.24 [mean +/- SE]%, p = 0.03) and with the degree of impairment in graft oxygenation after implantation (p = 0.01). An increased level of IL-8 in the donor BALF was associated with the development of severe early graft dysfunction (p = 0.027) and with early recipient mortality (p = 0.0034). Use of donor lungs with high IL-8 levels is associated with a poor prognosis after lung transplantation. Attenuating the donor's inflammatory response before organ retrieval may improve early outcome after lung transplantation, and help maximize lung use from the existing donor pool.

Bronchoalveolar Lavage Fluid↗
PubMed2001

The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS).

BACKGROUND: The acute respiratory distress syndrome (ARDS) represents a form of severe acute inflammatory lung disease. We have previously demonstrated significantly raised interleukin-8 (IL-8) levels in the lungs of at-risk patients that progress to ARDS, and identified the alveolar macrophage as an important source of this chemokine. We wished to extend this study in a well-defined group of patients with major trauma, and to investigate potential mechanisms for rapid intrapulmonary IL-8 generation. MATERIALS AND METHODS: Patients with major trauma underwent bronchoalveolar lavage (BAL) and IL-8 levels were measured in BAL fluid by ELISA. Human macrophages were derived from peripheral blood monocytes from healthy volunteers. Rabbit alveolar macrophages were obtained from ex-vivo lavage of healthy rabbit lungs. Macrophages were culture under normoxic or hypoxic (PO2 26 mmHg) conditions. IL-8 and other proinflammatory mediator expression was measured by ELISA, northern blotting or multi-probe RNase protection assay. RESULTS: In patients with major trauma, IL-8 levels were significantly higher in patients that progressed to ARDS compared to those that did not (n = 56, P = 0.0001). High IL-8 levels negatively correlated with PaO2/FiO2 (r = -0.56, P < 0.001). In human monocyte derived macrophages hypoxia rapidly upregulated IL-8 protein (within 2 hours) and mRNA expression (within 30 mins). Acute hypoxia also increased rabbit alveolar macrophage IL-8 expression. Hypoxia increased DNA binding activity of AP-1 and C/EBP but not NF-kappaB. Hypoxia induced HIF-1 expression, but cobaltous ions and desferrioxamine did not mimic hypoxic IL-8 induction. Hypoxia downregulated a range of other proinflammatory mediators, including MCP-1 and TNF-alpha. Both the pattern of cytokine expression and transcription factor activation by hypoxia was different to that seen with endotoxin. CONCLUSIONS: Rapidly raised intrapulmonary IL-8 levels are associated with ARDS progression in patients with major trauma. Acute hypoxia, a clinically relevant stimulus, rapidly and selectively upregulates IL-8 in macrophages associated with a novel pattern of transcription factor activation. Acute hypoxia may represent one of potentially several proinflammatory stimuli responsible for rapid intrapulmonary IL-8 generation in patients at-risk of ARDS.

Adolescent↗
PubMed2000

Temperature-dependent arrest of neutrophil apoptosis. Failure of Bax insertion into mitochondria at 15 degrees C prevents the release of cytochrome c.

Apoptosis is essential for the resolution of neutrophilic inflammation. To define the mechanisms triggering the execution phase of apoptosis we developed and utilized a model in which culture of human neutrophils at 15 degrees C for 20 h arrested apoptosis and subsequent warming to 37 degrees C triggered a synchronous burst of apoptosis. Treatment of 15 degrees C cultured neutrophils with the pan-caspase inhibitor zVAD-fmk just before warming to 37 degrees C inhibited the morphological changes associated with apoptosis, but did not prevent the insertion of the proapoptotic protein Bax into mitochondria nor the inhibition of secretion and the externalization of phosphatidylserine, indices of neutrophil apoptosis. In both intact neutrophils and a cell-free extract, cytochrome c released from mitochondria induced proteolytic cleavage of procaspase-3. At 15 degrees C the binding of Bax to mitochondria was uncoupled from Bax insertion into the mitochondrial membrane required for the release of cytochrome c. Apoptosis was also inhibited by low pH during warming to 37 degrees C, suggesting that changes to the conformation of Bax, necessary for membrane insertion, were being inhibited. Bax insertion was only sensitive to zVAD-fmk when added at the start of the 15 degrees C culture period, suggesting that a cytoplasmic substrate of the effector caspases may mediate in the mechanism of Bax insertion into mitochondria.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Soluble E-selectin acts in synergy with platelet-activating factor to activate neutrophil beta 2-integrins. Role of tyrosine kinases and Ca2+ mobilization.

Selectins play a critical role in neutrophil recruitment to sites of inflammation, in tethering and rolling of neutrophils on vascular endothelium, as well as triggering beta(2)-integrin-mediated adhesion. We have previously demonstrated potential pro-inflammatory effects of soluble E-selectin upon neutrophil effector functions, using a soluble recombinant molecule (E-zz), which increased beta(2)-integrin-mediated adhesion, decreased beta(2)-integrin-dependent migration, and triggered reactive oxygen species generation and release. In this study, we have examined the intracellular signals following neutrophil activation by soluble E-selectin. We show that exposure of neutrophils to E-selectin and platelet-activating factor (PAF) in combination induced a synergistic effect upon beta(2)-integrin-mediated adhesion. Although soluble E-selectin did not induce Ca(2+) mobilization in neutrophils by itself, elevation of intracellular Ca(2+) was specifically prolonged in response to PAF but not leukotriene B(4) or N-formyl-Met-Leu-Phe. The prolonged Ca(2+) mobilization observed in the presence of E-selectin was dependent on Ca(2+) influx from intracellular stores rather than influx of extracellular Ca(2+) through SKF 96365-sensitive channels. The specific alteration of Ca(2+) mobilization reported here appears not to have a role in the synergistic effects of E-selectin and PAF upon neutrophil O(2) release but may be involved in augmentation of beta(2)-integrin-mediated adhesion.

CD18 Antigens↗
PubMed2000

Induction of human neutrophil apoptosis by nitric oxide donors: evidence for a caspase-dependent, cyclic-GMP-independent, mechanism.

This study investigated the regulatory effects of the major inflammatory mediator, nitric oxide (NO), on human neutrophil apoptosis in vitro. Co-culture of human neutrophils with the NO donors GEA 3162 (1,2,3,4-oxatriazolium,5-amino-3-(3,4-dichlorophenyl)-chloride) (10-100 microM) and 3-morpholino-sydnonimine (SIN-1) (0.3-3 mM) caused a dramatic and concentration-dependent induction of apoptosis. However, N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced neutrophil activation (actin reorganization and chemotaxis) was inhibited by GEA 3162 treatment. The pro-apoptotic effects of the NO donors were (i) unaffected by the soluble guanylate cyclase inhibitor LY-83583 (6-anilino-5,8-quinolinedione; 100 microM), (ii) antagonized by superoxide dismutase (6 microg/mL), (iii) mimicked by exogenous peroxynitrite (at concentrations >100 microM), and (iv) inhibited by the caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone (100 microM). The pro-apoptotic effect of the NO donors was not mimicked by the cell-permeable cyclic nucleotide analogue, N6,2-O-dibutyrylguanosine-3',5'-cyclic monophosphate (dibutyryl-cGMP) at concentrations < or =0.2 mM. Indeed, at high concentrations (> or =2 mM), dibutyryl-cGMP caused an inhibition of apoptosis. These results suggest that NO-mediated apoptosis, although caspase-dependent, is mediated by a cGMP-independent mechanism and involves the concurrent generation of oxygen free radicals and, potentially, peroxynitrite. Our data reveal a unique role for NO in inflammatory responses with differential effects upon neutrophil activation and survival, with important implications for the successful resolution of inflammation.

Adult↗
PubMed2000

Molecular characterization of the surface of apoptotic neutrophils: implications for functional downregulation and recognition by phagocytes.

We have used a panel of monoclonal antibodies and lectins to examine the profile of surface molecule expression on human neutrophils that have undergone spontaneous apoptosis during in vitro culture. Neutrophil apoptosis was found to be accompanied by down-regulation of the immunoglobulin superfamily members PECAM-1 (CD31), ICAM-3 (CD50), CD66acde, and CD66b and the integrin-associated proteins CD63 and urokinase plasminogen activator receptor (CD87) that may alter the potential for adhesive interactions. Cellular interactions may be further influenced by the reduction of the expression of surface carbohydrate moieties, including sialic acid. Reduced expression of FcgammaRII (CD32), complement receptor type 1 (CD35) and receptors for pro-inflammatory mediators C5a (CD88) and TNFalpha (CD120b) associated with apoptosis might limit neutrophil responsiveness to stimuli that trigger degranulation responses. Although many of the receptors we have examined are expressed at reduced levels on apoptotic neutrophils, we found that there was differential loss of certain receptors (e.g. CD16, CD15 and CD120b) and increased expression of aminopeptidase-N (CD13). Together with our previous data showing that expression of certain molecules e.g. LFA-3 (CD58) is not altered during neutrophil apoptosis, these data are suggestive of specific changes in receptor mobilisation and shedding associated with apoptosis. Although reduced expression of CD63 (azurophilic granules) and CR1 (specific granules) indicates that granule mobilisation does not accompany apoptosis, a monoclonal antibody (BOB78), that recognises a 90 kDa antigen localised in intracellular granules, defines a subpopulation of apoptotic neutrophils that exhibit nuclear degradation yet retain intact plasma membranes. BOB78 positive neutrophils were found to bind biotinylated thrombospondin, suggesting that this mAb defines surface molecular changes associated with exposure of thrombospondin binding moieties.

Animals↗
PubMed2000

[Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) induces AP-1 transcription and sensitizes cells to chemotherapy.

[Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) inhibits small cell lung cancer (SCLC) growth and is entering Phase II clinical investigation for the treatment of SCLC. As well as acting as a neuropeptide receptor antagonist, antagonist G stimulates c-jun-N-terminal kinase (JNK) activity and apoptosis in SCLC cells. We extend these findings and show that the stimulation of JNK and apoptosis by antagonist G is dependent upon the generation of reactive oxygen species (ROS) being inhibited either by anoxia or the presence of N-acetyl cysteine (n-AC). Antagonist G is not intrinsically a free radical oxygen donor but stimulates free radical generation specifically within SCLC cells (6.2-fold) and increases the activity of the redox-sensitive transcription factor AP-1 by 61%. In keeping with this, antagonist G reduces cellular glutathione (GSH) levels (38% reduction) and stimulates ceramide production and lipid peroxidation (112% increase). At plasma concentrations achieved clinically in the phase I studies, antagonist G augments, more than additively, growth inhibition induced by etoposide. Our results suggest that antagonist G may be particularly effective as an additional treatment with standard chemotherapy in SCLC. These novel findings will be important for the clinical application of this new and exciting compound and for the future drug development of new agents to treat this aggressive cancer.

Acetylcysteine↗
PubMed2000

Pulmonary endothelial permeability and circulating neutrophil-endothelial markers in patients undergoing esophagogastrectomy.

OBJECTIVE: Esophagogastrectomy is an established surgical treatment for esophageal malignancy. The postoperative period may be complicated by the development of acute lung injury syndromes and thus, may provide a useful model in which to study the early pathogenic mechanisms of inflammatory lung injury. DESIGN: Open, prospective study. SETTING: High dependency and intensive therapy units. PATIENTS: Eight healthy male volunteers and 20 patients in the early postoperative period INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The lung protein accumulation index (PAI) of radiolabeled transferrin was determined by using a portable, double-isotope system. The following circulating inflammatory markers-thought to reflect neutrophil-endothelial activation and injury including circulating neutrophil elastase-soluble L-, E-, and P-selectins and thrombomodulin and von Willebrand factor antigen were assayed from venous blood samples The PAI for healthy volunteers was median -0.5 (range, -1.73 to 0.27) x 10(-3)/min and for patients undergoing esophagogastrectomy -0.005 (range, -1.53 to 2.28) x 10(-3)/min. There was no statistical difference between the two groups. In the postesophagogastrectomy group, a significant elevation in circulating levels of neutrophil elastase, soluble P- and E-selectin, thrombomodulin, and von Willebrand factor antigen were observed relative to the control group but only circulating plasma elastase demonstrated a significant correlation with the PAI (r2 = .23, p =.03). CONCLUSIONS: The data suggest patients undergoing esophagogastrectomy develop a inflammatory response but this is not a surrogate of permeability and other factors are likely to determine persistent injury to the alveolar-capillary barrier function in this patient group.

Aged↗
PubMed1999

Human neutrophil elastase regulates the expression and secretion of elafin (elastase-specific inhibitor) in type II alveolar epithelial cells.

Elafin is a low molecular weight antiproteinase believed to be important in the regulation of elastase mediated tissue damage. The expression of elafin is known to be regulated by proinflammatory cytokines such as interleukin-1 beta and tumour necrosis factor but little was known regarding the effect of human neutrophil elastase (HNE). Employing a chloramphenicol acetyltransferase reporter construct of the human elafin gene, reverse transcription PCR from total cellular RNA and ELISA techniques, we have examined the effect of human neutrophil elastase on the transcription and secretion of human elafin in the pulmonary epithelial A549 cell line. Stimulation with HNE at concentrations of 10(-10) and 10(-11) M resulted in a significant upregulation of elafin promoter activity. Similarly, transcription of the endogenous human elafin gene was upregulated with HNE concentrations ranging from 10(-10) to 10(-12) M. In addition, we demonstrate that stimulation with HNE at concentrations ranging from 10(-9) and 10(-12) M resulted in a significant reduction in the secreted elafin protein as measured in the cell supernatant. These results provide further evidence for a role of elafin in the regulation of HNE driven proteolysis of the extracellular matrix.

Cell Line↗
PubMed1999

Elafin (elastase-specific inhibitor) has anti-microbial activity against gram-positive and gram-negative respiratory pathogens.

Elafin (elastase-specific inhibitor) is a low molecular weight inhibitor of neutrophil elastase which is secreted in the lung. Using synthetic peptides corresponding to full-length elafin (H2N-1AVT.....95Q-OH), the NH2-terminal domain (H2N-1AVT.....50K-OH) and the COOH-terminal domain (H2N-51PGS.....95Q-OH), we demonstrate that elafin's anti-elastase activity resides exclusively in the COOH-terminus. Several characteristics of elafin suggest potential anti-microbial activity. The anti-microbial activity of elafin, and of its two structural domains, was tested against the respiratory pathogens Pseudomonas aeruginosa and Staphylococcus aureus. Elafin killed both bacteria efficiently, with 93% killing of P. aeruginosa by 2.5 microM elafin and 48% killing of S. aureus by 25 microM elafin. For both organisms, full-length elafin was required to optimise bacterial killing. These findings represent the first demonstration of co-existent anti-proteolytic and anti-microbial functions for elafin.

Antifungal Agents↗
PubMed1999

Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes.

Phagocyte recognition, uptake, and nonphlogistic degradation of neutrophils and other leukocytes undergoing apoptosis promote the resolution of inflammation. This study assessed the effects of anti-inflammatory glucocorticoids on this leukocyte clearance mechanism. Pretreatment of "semimature" 5-day human monocyte-derived macrophages (M phi) for 24 h with methylprednisolone, dexamethasone, and hydrocortisone, but not the nonglucocorticoid steroids aldosterone, estradiol, and progesterone, potentiated phagocytosis of apoptotic neutrophils. These effects were specific in that the potentiated phagocytosis of apoptotic neutrophils was completely blocked by the glucocorticoid receptor antagonist RU38486, and glucocorticoids did not promote 5-day M phi ingestion of opsonized erythrocytes. Similar glucocorticoid-mediated potentiation was observed with 5-day M phi uptake of alternative apoptotic "targets" (eosinophils and Jurkat T cells) and in uptake of apoptotic neutrophils by alternative phagocytes (human glomerular mesangial cells and murine M phi elicited into the peritoneum or derived from bone marrow). Importantly, methylprednisolone-mediated enhancement of the uptake of apoptotic neutrophils did not trigger the release of the chemokines IL-8 and monocyte chemoattractant protein-1. Furthermore, longer-term potentiation by methylprednisolone was observed in maturing human monocyte-derived M phi, with greater increases in 5-day M phi uptake of apoptotic cells being observed the earlier glucocorticoids were added during monocyte maturation into M phi. We conclude that potentiation of nonphlogistic clearance of apoptotic leukocytes by phagocytes is a hitherto unrecognized property of glucocorticoids that has potential implications for therapies aimed at promoting the resolution of inflammatory diseases.

Animals↗
PubMed1999

NF-kappaB activation is a critical regulator of human granulocyte apoptosis in vitro.

During beneficial inflammation, potentially tissue-damaging granulocytes undergo apoptosis before being cleared by phagocytes in a non-phlogistic manner. Here we show that the rate of constitutive apoptosis in human neutrophils and eosinophils is greatly accelerated in both a rapid and concentration-dependent manner by the fungal metabolite gliotoxin, but not by its inactive analog methylthiogliotoxin. This induction of apoptosis was abolished by the caspase inhibitor zVAD-fmk, correlated with the inhibition of nuclear factor-kappa B (NF-kappaB), and was mimicked by a cell permeable inhibitory peptide of NF-kappaB, SN-50; other NF-kappaB inhibitors, curcumin and pyrrolidine dithiocarbamate; and the proteasome inhibitor, MG-132. Gliotoxin also augmented dramatically the early (2-6 h) pro-apoptotic effects of tumor necrosis factor-alpha (TNF-alpha) in neutrophils and unmasked the ability of TNF-alpha to induce eosinophil apoptosis. In neutrophils, TNF-alpha caused a gliotoxin-inhibitable activation of an inducible form of NF-kappaB, a response that may underlie the ability of TNF-alpha to delay apoptosis at later times (12-24 h) and limit its early killing effect. Furthermore, cycloheximide displayed a similar capacity to enhance TNF-alpha induced neutrophil apoptosis even at time points when cycloheximide alone had no pro-apoptotic effect, suggesting that NF-kappaB may regulate the production of protein(s) which protect neutrophils from the cytotoxic effects of TNF-alpha. These data shed light on the biochemical and molecular mechanisms regulating human granulocyte apoptosis and, in particular, indicate that the transcription factor NF-kappaB plays a crucial role in regulating the physiological cell death pathway in granulocytes.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Pharmacological manipulation of granulocyte apoptosis: potential therapeutic targets.

Resolution of inflammation involves the clearance of excess or effete inflammatory cells by a process of physiological programmed cell death (apoptosis) and the subsequent recognition and removal of apoptotic cells by phagocytes. The therapeutic induction of apoptosis for the resolution of chronic inflammation and the general pharmacology of apoptosis have become subjects of increasing interest. In this article, some of the unique and important differences in the control of apoptosis of various inflammatory cells (particularly neutrophil and eosinophil granulocytes) are highlighted. It is suggested that apoptosis can be specifically regulated pharmacologically and could be exploited to develop new drug therapies.

Apoptosis↗
PubMed1999

Secretory leukocyte proteinase inhibitor is preferentially increased in patients with acute respiratory distress syndrome.

Inappropriate release of proteases from inflammatory and stromal cells can lead to destruction of the lung parenchyma. Antiproteinases such as alpha-1-proteinase inhibitor (alpha1-Pi), secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (elafin) control excess production of human neutrophil elastase. In the present study, the concentrations of alpha1-Pi, SLPI and elafin found in bronchoalveolar lavage (BAL) fluid from control subjects, patients at risk of developing acute respiratory distress syndrome (ARDS) and patients with established ARDS were determined. Levels of all three inhibitors were raised in patients compared with normal subjects. SLPI was increased in the group of patients who were at risk of ARDS and went on to develop the condition, compared with the "at-risk" group who did not progress to ARDS (p=0.0083). Alpha1-Pi and elafin levels were similar in these two populations. In patients with established ARDS, both alpha1-Pi and SLPI levels were significantly increased, compared to patients at risk of ARDS who did (p=0.0089) or did not (p=0.0003) progress to ARDS. The finding of increased antiproteinases shortly before the development of acute respiratory distress syndrome provide further evidence for enhanced inflammation prior to clinical disease.

Bronchoalveolar Lavage Fluid↗
PubMed1999

Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo.

Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of beta1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking beta1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.

Amino Acid Chloromethyl Ketones↗
PubMed1999

[Arg6,D-Trp7,9,NmePhe8]-substance P (6-11) activates JNK and induces apoptosis in small cell lung cancer cells via an oxidant-dependent mechanism.

[Arg6,D-Trp7,9,NmePhe8]-substance P (6-11) (antagonist G) is a novel class of anti-cancer agent that inhibits small-cell lung cancer (SCLC) cell growth in vitro and in vivo and is entering phase II clinical investigation for the treatment of SCLC. Although antagonist G blocks SCLC cell growth (IC50 = 24.5 +/- 1.5 and 38.5 +/- 1.5 microM for the H69 and H510 cell lines respectively), its exact mechanism of action is unclear. This study shows that antagonist G stimulates apoptosis as assessed by morphology (EC50 = 5.9 +/- 0.1 and 15.2 +/- 2.7 microM for the H69 and H510 cell lines respectively) and stimulates c-jun-N-terminal kinase (JNK) activity in SCLC cells (EC50 = 3.2 +/- 0.1 and 15.2 +/- 2.7 microM). This activity is neuropeptide-independent, but dependent on the generation of reactive oxygen species (ROS) and is inhibited by the free radical scavenger n-acetyl cysteine. Furthermore, antagonist G itself induces inflammation (59% increase in oedema volume compared to control) and potentiates (by 35-40%) bradykinin-induced oedema formation in vivo. In view of these results we show that, as well as acting as a 'broad-spectrum' neuropeptide antagonist, antagonist G stimulates basal G-protein activity in SCLC cell membranes (81 +/- 12% stimulation at 10 microM), thereby displaying a unique ability to stimulate certain signal transduction pathways by activating G-proteins. This novel activity may be instrumental for full anti-cancer activity in SCLC cells and may also account for antagonist G activity in non-neuropeptide-dependent cancers.

3T3 Cells↗
PubMed1999

Initial serum ferritin levels in patients with multiple trauma and the subsequent development of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) represents a catastrophic form of inflammatory lung injury that occurs unpredictably in some, but not all, at-risk patients. In this study, we investigated serum ferritin as a marker for ARDS development in a homogenous group of patients at-risk because of multiple trauma. We hypothesized that since ferritin synthesis is increased by proinflammatory cytokines, which are increased and implicated in ARDS, that ferritin levels would increase and that ferritin increases would correlate with the degree of inflammation and therefore the development of ARDS. We studied 42 patients (25 male, 17 female) who as a consequence of multiple trauma became at-risk for developing ARDS. Using the European/American Consensus definition for ARDS, 16 (38%) patients subsequently developed ARDS (11 male and five female). We found that initial serum ferritin levels correlated with the subsequent development of both ARDS (progression to ARDS, median = 638 ng/ml; (range, 70 to 4,500) versus nonprogression to ARDS = 185 ng/ml; range, 12 to 2,850) (p = 0.02, r = -0.27) and multiple organ failure (p < 0.05, r = 0.39). Using our previously established cutoff points for serum ferritin, the positive predictive value was 62% for men and 75% for women. Initial serum ferritin levels also correlated with a measurement of the degree of initial trauma injury, i.e., the injury severity score (ISS) (p < 0.05, r = 0.37). However, there was no correlation between serum ferritin levels and other markers of clinical injury, namely, lowest PaO2/FIO2 ratio (p = 0.67), days requiring ventilation (p = 0.09), or mortality (p = 0.42). A significant association existed between serum ferritin levels and products of endothelial activation, i.e., sE-selectin (p < 0.04, r = 0.37) and sICAM-1 (p < 0.01, r = 0.21). In the future, with the development of novel anti-inflammatory therapies, early identification of specific high-risk patients would allow the institution of these therapies and thereby increase the chances of reducing ARDS morbidity and mortality.

Acute Disease↗