P.G. Jorens

Potential role of Clara cell protein, an endogenous phospholipase A2 inhibitor, in acute lung injury

It is now recognized that epithelial cells lining airways and alveoli are capable of releasing various mediators, which have the potential to modulate local inflammatory reactions. The amount of the 16 kDa Clara cell protein (CC16), an inhibitor of phospholipase A2 activity produced by pulmonary epithelial cells, was measured by means of a sensitive immunoassay in the unconcentrated bronchoalveolar lavage fluid (BALF) of 13 control subjects, and in patients with acute lung injury (14 with the full-blown adult respiratory distress syndrome (ARDS); 21 after standard cardiopulmonary bypass surgery, a known risk factor for ARDS). The level of CC16 was compared with other markers of inflammation with a wide range of molecular weights: albumin (nephelometry); total protein (spectrophotometry); beta 2-microglobulin (latex immunoassay); cystatin C (latex immunoassay); alpha 1-antitrypsin (immunoradiometry), and lipocortin-1 (enzyme-linked immunosorbent assay (ELISA)). The Clara cell protein (CC16) was detectable in all BALF, and significantly higher levels of this protein were observed in BALF from patients with acute lung injury. Changes in BALF Clara cell protein levels differed from those of alpha 2-macroglobulin and the natural phospholipase inhibitor lipocortin-1. Alpha 2-macroglobulin levels were not significantly enhanced in patients at risk for ARDS, but were increased in patients with ARDS; whereas, lipocortin 1 levels were not elevated in either group. Pretreatment of patients at risk for ARDS with high dose methylprednisolone did not alter the amount of Clara cell protein recovered in BALF. The mean CC16 level in BALF from patients with ARDS who died was significantly lower than from those who survived. The data presented in this study suggest that pulmonary epithelial cells secrete a natural anti-inflammatory protein during acute lung injury, which might have a protective and immunosuppressive role.

N-acetylcysteine pretreatment of cardiac surgery patients influences plasma neutrophil elastase and neutrophil influx in bronchoalveolar lavage fluid

ObjectiveStudy of leukocyte activation and release of toxic mediators during extracorporeal circulation (ECC). ECC can be used to study the potential protective effect of a pharmacon against neutrophil-mediated lung injury. Clinical studies have indicated that N-acetylcysteine (NAC) may improve systemic oxygenation and reduce the need for ventilatory support when given to patients with acute lung injury.DesignCardiac surgery patients were pretreated with high-dose NAC in order to assess the potential role of NAC to interfere with neutrophil-mediated inflammation and lung injury.Patients18 patients who underwent ECC: group 1 (n=8) no premedication (only placebo); group 2 (n=10) NAC (72 mg/kg i.v. as a bolus, later 72 mg/kg over 12 h).Measurements and resultsIn group 2, the partial pressure of oxygen in arterial blood/fractional inspired oxygen 4 h after surgery was significantly higher than in group 1 (213±31 vs 123±22;p=0.044). NAC pretreatment prevented an increase in plasma neutrophil elastase activity (18.9±6.9 vs 49.9±5.6 ng/ml in group 1 at the end of ECC;p=0.027). Release of myeloperoxidase (MPO) was not affected (group 1: 1105±225 ng/ml vs group 2: 1127±81 at the end of ECC;p=0.63). At the end of ECC, total antigenic human neutrophil elastase (group 1: 671±72 ng/ml vs group 2: 579±134;p=0.37) and complex formation between elastase and α1-proteinase inhibitor were no different in the two groups. There were no significant differences in cellular composition and mediators in the lavage fluid, although values for total number of neutrophils, elastase, MPO and interleukin-8 were lower in group 2.ConclusionPretreatment with NAC may prevent lung injury by diminishing elastase activity. Since the release of mediators, especially MPO, is not affected, this diminished activity of elastase may be achieved by enhanced inactivation by antiproteases after initial treatment.

Acute poisoning with amphetamines (MDEA) and heroin: antagonistic effects between the two drugs

A case of oral ingestion of large doses of both the amphetamine-derivative 3,4-methylene dioxyethamphetamine (MDEA) and heroin is reported. Despite high serum levels of both drugs, the patient did not present with the classic signs and symptoms normally seen during intoxication with these drugs. The patient recovered after symptomatic treatment. The possibility that opposite pharmacological properties of the two drugs prevented the patients death is discussed.

Pretreatment with methylprednisolone in coronary artery bypass grafting influences the levels of histamine and tryptase in serum but not in bronchoalveolar lavage fluid.

1. The presence of histamine and tryptase in serum during and after coronary artery bypass grafting may be an indication of the induction of inflammation. 2. One group of patients received no glucocorticoids and a second group received methylprednisolone before extracorporeal circulation. In the steroid group no effects were seen on the basal levels of histamine (2.84 +/- 0.12 ng/ml) and tryptase (0.50 +/- 0.05 ng/ml) during and after surgery. In the other group two peak levels of histamine were observed: one at 10 min after starting extracorporeal circulation (4.19 +/- 1.79 ng/ml) and another at 4 h after surgery (8.26 +/- 4.85 ng/ml). In this group tryptase was only elevated during the period of extracorporeal circulation (1.54 +/- 0.16 ng/ml). 3. There were no differences between the two groups in complement activation. C3a levels rose to 170 +/- 8% and 180 +/- 10% of the initial value in the steroid and non-steroid group, respectively. 4. It was concluded that during surgery mast cells were activated, but since tryptase levels decreased in the post-operative period, the second increase in the histamine level can be explained by activation of basophils or by an unknown mechanism for the release of histamine but not tryptase by mast cells. 5. In the bronchoalveolar lavage fluid the levels of histamine and tryptase showed no differences between the two groups of patients, but histamine was enhanced compared with normal levels.

Release of arachidonic acid metabolites from isolated human alveolar type II cells

Human alveolar type II cells are thought to play a role in the pathogenesis of lung injury. Patterns of mediator release of arachidonic acid metabolism by type II cells were therefore studied after challenge with calcium ionophore A23187, opsonized zymosan and hydrogen peroxide. A time- and concentration dependent release of cyclooxygenase products was observed, with release of PGE2 greater than 6-keto-PGF1 alpha greater than TxB2. Addition of glutathione or bicarbonate further increased the production of PGE2. N-ethylmaleimide, a sulfhydryl (SH) reactant, induced a dose-dependent increase in the release of TxB2 and 6-keto-PGF1 alpha, but not of PGE2. This relates most likely to the SH-dependency and glutathione requirement of the PGE2 isomerase and SH-independence of thromboxane and prostacyclin isomerase.

Stridor due to a bridge-like subglottic stenosis in a 10-week-old male infant

We present an infant with post-intubation stridor caused by a bridge-like subglottic stenosis. At the age of 6 weeks he suffered from a RSV infection with the need for endotracheal intubation. At week 10 acute respiratory distress required a re-intubation. Flexible endoscopy was suggestive for laryngomalacia. Rigid endoscopy revealed a subglottic laterolateral mucosal bridge resulting in a doubling of the airway lumen. Histopathological examination showed a fibrinoid pseudomembrane. Follow up endoscopy showed a grade 1 posterior subglottic stenosis without respiratory compromise. This is the first case in the literature of an infant with a post-intubation bridge-like fibrinoid pseudomembranous subglottic lesion.

Angiotensin-converting enzyme activity in serum and bronchoalveolar lavage fluid after damage to the alveolo-capillary barrier in the human lung

ObjectiveAngiotensin-converting enzyme (ACE) is considered as a possible marker for endothelial cell damage in serum or bronchoalveolar lavage fluid. This hypothesis was tested during cardiac surgery and during the adult respiratory distress syndrome.DesignWe used patients with an expected different degree of endothelial cell damage. ACE levels in serum and bronchoalveolar lavage fluid were compared with indirect markers of alveolo-capillary barrier integrity.SettingInterdisciplinary team in a university hospital.Methods13 Cardiac surgery patients received no glucocorticoids and 13 others received 2g methylprednisolone before extracorporeal circulation. Thirteen patients were used as controls and 15 patients had nonseptic adult respiratory distress syndrome. All underwent bronchoalveolar lavage for ACE determination.ResultsAt different times during surgery serum angiotensin-converting enzyme levels were not significantly different between the two groups. In post-operative bronchoalveolar lavage fluid, angiotensin-converting enzyme levels were significantly higher in patients who received corticoids (27.8±1.7U/1, mean±SEM), compared to patients without corticoids (19.8±1.4U/1), control patients (18.2±1.3U/1) or patients with full blown non-septic adult respiratory distress syndrome (18.8±1.1U/1). There were no correlations between lavage angiotensin-converting enzyme and other parameters for alveolo-capillary membrane integrity in the lavage fluid such as the number of neutrophil cells, albumin or protein concentration, and between lavage angiotensin-converting enzyme and PaO2/FIO2 ratio during lavage.ConclusionAngiotensin-converting enzyme activity in serum or bronchoalveolar lavage fluid does not reflect damage of endothelial cells or damage of alveolocapillary integrity in acute pulmonary disease.

Tumor necrosis factor — a novel stimulus for human skin mast cells to secrete histamine and tryptase

Mast cells from infant foreskin obtained during circumcision were dispersed by an enzymatic technique, pooled, washed and purified. Mast cells, with a purity of 70–90% were incubated with 10−11 to 10−7M rTNFα. Histamine and tryptase levels were assessed in the cell supernatant and a concentration dependent release of histamine was observed. Histamine reached a maximum of 11.5±2.2 nmol/106 cells at 10−8M rTNF. Tryptase reached a maximum of 293±105 mU/106 cells (10−8M rTNF). rTNFα thus appears to be a direct stimulus for mast cells to degranulate and to release both histamine and tryptase.

Evidence for marked eosinophil degranulation in a case of eosinophilic pneumonia

*Department of Respiratory Medicine, University Hospital of Antwerp and i-Department of Internal Medicine, St Anna Hospital, Beveven, Belgium Introduction Eosinophils are inflammatory cells which are believed to play a key role in a variety of inflamma- tory conditions, including parasitic and allergic dis- eases. These cells are cytotoxic to parasites and mammalian cells, and can modulate the function of other cells. After activation, they are able to produce and release lipid-derivatives, oxygen free radicals and cytotoxic-granule-derived proteins. The presence of these eosinophilic cationic proteins, including eosinophil cationic protein (ECP), major basic pro- tein (MBP), eosinophil peroxidase and eosinophilic protein X (EPX, also called eosinophil-derived neurotoxin), in biological fluids or inflammatory tissues is accepted as a marker of eosinophilic activation (1). Although a high number of eosinophils are found both in the peripheral circulation and the broncho- alveolar lavage (BAL) fluid of patients with eosino- philic pneumonia, little is known about the extent of eosinophil degranulation encountered in this dis- order. The present case report describes a patient with eosinophilic pneumonia in whom high serum levels of both ECP and EPX were observed, as well as a high level in the BAL fluid, indicating that marked eosinophil degranulation had taken place. Materials and Methods

ICP and CPP management before and after 2007: impact on the association between dose of ICP and outcome

In a recent paper, the intracranial pressure-time burden associated with worse outcome in traumatic brain injury (TBI) patients was visualised in a color-coded plot [1]. This color-coded plot illustrates the intuitive concept that episodes of higher intracranial pressure (ICP) can only be tolerated for shorter durations: the transition curve that delineates the duration and intensity of those ICP episodes associated with worse outcome is an approximately exponential decay curve. The study was done in a large prospective multicenter European cohort of patients, including patients from before and after 2007. In 2007, the guidelines on cerebral perfusion pressure (CPP) management in severe TBI have changed [2].