Data accuracy, consistency and completeness of the national Swiss cystic fibrosis patient registry: Lessons from an ECFSPR data quality project.

BACKGROUND: Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research. METHODS: All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed. RESULTS: The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with <5 % for almost all variables. A considerable number of missing source data occurred for CFTR variants. Availability of ICs varied largely between centers (10 centers had >5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved. CONCLUSIONS: Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research.

Standardization of Reporting Obstructive Airway Disease in Children: A National Delphi Process.

BACKGROUND: Pediatric pulmonologists report asthma and obstructive bronchitis in medical records in a variety of ways, and there is no consensus for standardized reporting. OBJECTIVE: We investigated which diagnostic labels and features pediatric pulmonologists use to describe obstructive airway disease in children and aimed to reach consensus for standardized reporting. METHODS: We obtained electronic health records from 562 children participating in the Swiss Pediatric Airway Cohort from 2017 to 2018. We reviewed the diagnosis section of the letters written by pediatric pulmonologists to referring physicians and extracted the terms used to describe the diagnosis. We grouped these terms into diagnostic labels (eg, asthma) and features (eg, triggers) using qualitative thematic framework analysis. We also assessed how frequently the different terms were used. Results were fed into a modified Delphi process to reach consensus on standardized reporting. RESULTS: Pediatric pulmonologists used 123 different terms to describe the diagnosis, which we grouped into 6 diagnostic labels and 17 features. Consensus from the Delphi process resulted in the following recommendations: (i) to use the diagnostic label "asthma" for children older than 5 years and "obstructive bronchitis" or "suspected asthma" for children younger than 5 years; (ii) to accompany the diagnosis with relevant features: diagnostic certainty, triggers, symptom control, risk of exacerbation, atopy, treatment adherence, and symptom perception. CONCLUSION: We found great heterogeneity in the reporting of obstructive airway disease among pediatric pulmonologists. The proposed standardized reporting will simplify communication among physicians and improve quality of research based on electronic health records.

Treatment Decisions in Children With Asthma in a Real-Life Clinical Setting: The Swiss Paediatric Airway Cohort.

BACKGROUND: Asthma treatment should be modified according to symptom control and future risk, but there are scarce data on what drives treatment adjustments in routine tertiary care. OBJECTIVE: We studied factors that drive asthma treatment adjustment in pediatric outpatient clinics. METHODS: We performed a cross-sectional analysis of the Swiss Paediatric Airway Cohort, a clinical cohort of 0- to 16-year-old children seen by pediatric pulmonologists. We collected information on diagnosis, treatment, lung function, and FeNO from hospital records; and on symptoms, sociodemographic, and environmental factors from a parental questionnaire. We used reported symptoms to classify asthma control and categorized treatment according to the 2020 Global Initiative for Asthma guidelines. We used multivariable logistic regression to study factors associated with treatment adjustment (step-up or down vs no change). RESULTS: We included 551 children diagnosed with asthma (mean age, 10 years; 37% female). At the clinical visit, most children were prescribed Global Initiative for Asthma step 3 (35%). Compared with previsit treatment, 252 children remained on the same step (47%), 227 were stepped up (42%), and 58 were stepped down (11%). Female sex (adjusted odds ratio [aOR] = 1.61; 95% confidence interval [CI], 1.05-2.47), poor asthma control (aOR = 3.08; 95% CI, 1.72-5.54), and lower FEV1 Z-score (aOR = 0.70; 95% CI, 0.56-0.86 per one Z-score increase) were independently associated with treatment step-up, and low FeNO (aOR = 2.34; 95% CI, 1.23-4.45) was associated with treatment step-down, with marked heterogeneity between clinics. CONCLUSIONS: In this tertiary care real-life study, we identified main drivers for asthma treatment adjustment. These findings may help improve both asthma management guidelines and clinical practice.

Monocyclometalated (C

Invited for the cover of this issue are Koushik Venkatesan and co-workers at Macquarie University and the University of Zurich. The image depicts the conversion of 3 O2 to 1 O2 upon photoexcitation by new monocyclometalated gold(III) metallacycles. Read the full text of the article at 10.1002/chem.202102331.

Monocyclometalated (C N) Gold(III) Metallacycles: Tunable Emission and Singlet Oxygen (1 O2 ) Generation Properties.

The synthesis, characterization and photoluminescent properties of four cyclometalated (C N)-type gold(III) complexes bearing a bidentate diacetylide ligand, tolan-2,2'-diacetylide (tda), are reported. The complexes exhibit highly tunable excited state properties and show photoluminescence (PL) across the entire visible spectrum from sky-blue (λPL =493 nm) to red (λPL =675 nm) with absolute PL quantum yields (PLQY) of up to 75 % in solution, the highest PLQY found for any monocyclometalated Au(III) complex in solution. As a consequence of the use of the strongly rigidifying diacetylide bidentate ligand, a significant increase in the excited state lifetimes (τ0 =16-258 µs) was found in solution and in thin films. The complexes showed remarkable singlet oxygen generation in aerated solution with absolute singlet oxygen quantum yield (ϕ1Δ ) values reaching up to 7.5×10-5 and singlet oxygen lifetimes (τ0 1Δ ) in the range of 66-95 µs. Furthermore, the radiative and non-radiative rates of singlet oxygen were determined using the ϕ1Δ and τ0 1Δ values and correlations are drawn between the formation of singlet oxygen and its interaction with cyclometalated (C N) gold(III) complexes.

Respiratory symptoms do not reflect functional impairment in early CF lung disease.

BACKGROUND: Lung disease can develop within the first year of life in infants with cystic fibrosis (CF). However, the frequency and severity of respiratory symptoms in infancy are not known. METHODS: We assessed respiratory symptoms in 50 infants with CF and 50 healthy matched controls from two prospective birth cohort studies. Respiratory symptoms and respiratory rate were documented by standardized weekly interviews throughout the first year. Infants performed multiple breath washout in the first weeks of life. RESULTS: We analyzed 4552 data points (2217 in CF). Respiratory symptoms (either mild or severe) were not more frequent in infants with CF (OR:1.1;95% CI:[0.76, 1.59]; p=0.6). Higher lung clearance index and higher respiratory rate in infants with CF were not associated with respiratory symptoms. CONCLUSIONS: We found no difference in respiratory symptoms between healthy and CF infants. These data indicate that early CF lung disease may not be captured by clinical presentation alone.

Reported Symptoms Differentiate Diagnoses in Children with Exercise-Induced Respiratory Problems: Findings from the Swiss Paediatric Airway Cohort (SPAC).

BACKGROUND: Exercise-induced breathing problems with similar clinical presentations can have different etiologies. This makes distinguishing common diagnoses such as asthma, extrathoracic and thoracic dysfunctional breathing (DB), insufficient fitness, and chronic cough difficult. OBJECTIVE: We studied which parent-reported, exercise-induced symptoms can help distinguish diagnoses in children seen in respiratory outpatient clinics. METHODS: This study was nested in the Swiss Paediatric Airway Cohort, an observational study of children aged 0 to 17 years referred to pediatric respiratory outpatient clinics in Switzerland. We studied children aged 6 to 17 years and compared information on exercise-induced symptoms from parent-completed questionnaires between children with different diagnoses. We used multinomial regression to analyze whether parent-reported symptoms differed between diagnoses (asthma as base). RESULTS: Among 1109 children, exercise-induced symptoms were reported for 732 (66%) (mean age: 11 years, 318 of 732 [43%] female). Among the symptoms, dyspnea best distinguished thoracic DB (relative risk ratio [RRR]: 5.4, 95% confidence interval [CI]: 1.3-22) from asthma. Among exercise triggers, swimming best distinguished thoracic DB (RRR: 2.4, 95% CI: 1.3-6.2) and asthma plus DB (RRR: 1.8, 95% CI: 0.9-3.4) from asthma only. Late onset of symptoms was less common for extrathoracic DB (RRR: 0.1, 95% CI: 0.03-0.5) and thoracic DB (RRR: 0.4, 95% CI: 0.1-1.2) compared with asthma. Localization of dyspnea (throat vs chest) differed between extrathoracic DB (RRR: 2.3, 95% CI: 0.9-5.8) and asthma. Reported respiration phase (inspiration or expiration) did not help distinguish diagnoses. CONCLUSION: Parent-reported symptoms help distinguish different diagnoses in children with exercise-induced symptoms. This highlights the importance of physicians obtaining detailed patient histories.

Diagnosis in children with exercise-induced respiratory symptoms: A multi-center study.

OBJECTIVE: Exercise-induced respiratory symptoms (EIS) are common in childhood and reflect different diseases that can be difficult to diagnose. In children referred to respiratory outpatient clinics for EIS, we compared the diagnosis proposed by the primary care physician with the final diagnosis from the outpatient clinic and described diagnostic tests and treatments. DESIGN: An observational study of respiratory outpatients aged 0-16 years nested in the Swiss Paediatric Airway Cohort (SPAC). PATIENTS: We included children with EIS as the main reason for referral. Information about diagnostic investigations, final diagnosis, and treatment prescribed came from outpatient records. We included 214 children (mean age 12 years, range 2-17, 54% males) referred for EIS. RESULTS: The final diagnosis was asthma in 115 (54%), extrathoracic dysfunctional breathing (DB) in 35 (16%), thoracic DB in 22 (10%), asthma plus DB in 23 (11%), insufficient fitness in 10 (5%), chronic cough in 6 (3%), and other diagnoses in 3 (1%). Final diagnosis differed from referral diagnosis in 115 (54%, 95%-CI 46%-60%). Spirometry, body plethysmography, and exhaled nitric oxide were performed in almost all, exercise-challenge tests in a third, and laryngoscopy in none. 91% of the children with a final diagnosis of asthma were prescribed inhaled medication and 50% of children with DB were referred to physiotherapy. CONCLUSIONS: Diagnosis given at the outpatient clinic often differed from the diagnosis proposed by the referring physician. Diagnostic evaluations, management, and follow-up differed between clinics and diagnostic groups highlighting the need for evidence-based diagnostic guidelines and harmonized procedures for children seen for EIS.

Diagnosis of asthma in children: findings from the Swiss Paediatric Airway Cohort.

INTRODUCTION: Diagnosing asthma in children remains a challenge because respiratory symptoms are not specific and vary over time. AIM: In a real-life observational study, we assessed the diagnostic accuracy of respiratory symptoms, objective tests and two paediatric diagnostic algorithms (proposed by the Global Initiative for Asthma (GINA) and the National Institute for Health and Care Excellence (NICE)) in the diagnosis of asthma in school-aged children. METHODS: We studied children aged 5-17 years who were referred consecutively to pulmonary outpatient clinics for evaluation of suspected asthma. Symptoms were assessed by parental questionnaire. The investigations included specific IgE measurement or skin prick tests, measurement of exhaled nitric oxide fraction (F eNO), spirometry, body plethysmography and bronchodilator reversibility (BDR). Asthma was diagnosed by paediatric pulmonologists based on all available data. We assessed diagnostic accuracy of symptoms, tests and diagnostic algorithms by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the curve (AUC). RESULTS: Among 514 participants, 357 (70%) were diagnosed with asthma. The combined sensitivity and specificity was highest for any wheeze (sensitivity=75%, specificity=65%), dyspnoea (sensitivity=56%, specificity=76%) and wheeze triggered by colds (sensitivity=58%, specificity=78%) or by exercise (sensitivity=55%, specificity=74%). Of the diagnostic tests, the AUC was highest for specific total airway resistance (sRtot; AUC=0.73) and lowest for the residual volume (RV)/total lung capacity (TLC) ratio (AUC=0.56). The NICE algorithm had sensitivity=69% and specificity=67%, whereas the GINA algorithm had sensitivity=42% and specificity=90%. CONCLUSION: This study confirms the limited usefulness of single tests and existing algorithms for the diagnosis of asthma. It highlights the need for new and more appropriate evidence-based guidance.

Highly Stable and Strongly Emitting N-Heterocyclic Carbene Platinum(II) Biaryl Complexes.

C^C cyclometalated platinum(II) triplet emitters bearing electronically different N-heterocyclic carbenes-(1,3-diisopropyl-4-(trifluoromethyl)-imidazol-2-ylidene (d), 1,3-diisopropyl-benzimidazol-2-ylidene (e), and 1,3-diisopropyl-imidazol-2-ylidene (f))-as neutral ligands and biphenyl (bph) as well as its fluorinated derivative octafluorobiphenyl (oFbph) as dianionic cyclometalating ancillary ligand were synthesized and structurally characterized by 1H, 13C, 19F, and 195Pt NMR, single crystal X-ray diffraction, and HR-ESI-MS studies. Detailed photophysical investigations carried out reveal a strong influence on the excited-state properties exerted by the electronic nature of the N-heterocyclic carbenes as well as the fluorine functional groups on the ancillary biphenyl moiety. The solid-state structures of all complexes reveal a nearly planar and slightly distorted square planar geometry around the platinum center. Introduction of fluorine groups into the ligand framework leads to a less structured emission centered at 513 nm in poly(methyl methacrylate) (PMMA) thin films, compared to the highly structured emission profile of the bph analogues. Additionally, a hypsochromic shift of approximately 10-12 nm was found in the absorption as well as in the emission profiles and is attributed to the electron deficient nature of the oFbph ligand. Three wt % of the compounds doped in PMMA exhibit photoluminescence efficiencies as high as 92% in thin films. DFT and TD-DFT calculations on selected molecules revealed the charge transfer to be an admixture of intraligand (3ILCT) and metal-to-ligand charge transfer (3MLCT) and the frontier orbitals corresponding to the emission to be mainly localized on the bph and oFbph ligands, which is consistent with the observations from the photophysical investigations. The thermal stability of the complexes evaluated by thermogravimetric analysis (TGA) shows an enhanced thermal stability for the complexes bearing fluorine functional groups.

Computed tomography imaging for the characterisation of drugs with radiation density measurements and HU spectroscopy.

AIMS OF THE STUDY: To investigate the computed tomography (CT) density of frequently administered medications (1) for the better characterisation of substances on abdominal CT, (2) to allow radiologists to narrow down possibilities in the identification of hyperdense material in the bowel and (3) to provide forensic doctors with a tool to identify gastric contents before an autopsy. MATERIAL AND METHODS: From the list of the local hospital pharmacy, the 50 most frequently used medications were identified and scanned twice with a 128 row CT scanner (Acquillion, Toshiba, Tokyo, Japan). The protocol comprised two tube voltages of 100 kVp and 120 kVp, with a tube current of 100 mAs, a collimation of 0.5 mm and a slice thickness of 0.5 mm. Two readers were asked to measure the density (in Hounsfield units) and the noise (standard deviation of the Hounsfield units) of each pill in the two scans (100/120 kVp). After 4 weeks, both readers repeated the measurements to test repeatability (intra-rater agreement). The behaviour of each pill in hydrochloric acid (pH 2) was examined and the dissolution time was determined. RESULTS: The most dense pill was Cordarone (7265 HU), and the least was Perenterol (529 HU), with an attenuation that was lower than fat density (<120 HU). The standard deviation of pixel density (noise) reflects inhomogeneity of the pharmacological product, varying from 9 to 1592 HU among the different pills (at 120 kVp). The absolute average HU increase per pill when changing to lower voltage was 78 ± 253 HU, with a linear fitting line with a slope of 0.21 as a constant variable in the density spectroscopy. After 4 hours in hydrochloric acid, only six tablets were still intact, including Flagyl and Dafalgan. The intra- and inter-rater agreements for all measurements were nearly perfect, with a correlation coefficient r of ≥0.99 (p <0.0001). CONCLUSION: Our data suggest that measuring the attenuation of drugs on CT images, including the homogeneity, and applying CT spectroscopy can narrow down possible identities of the most frequently medications. Other clinicians and forensic pathologists can perform this easy measurement, as the intra- and inter-reader variability is very small.

Lower exhaled nitric oxide in infants with Cystic Fibrosis compared to healthy controls.

Exhaled nitric oxide (FENO) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FENO is decreased. To understand if reduced FENO is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FENO in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FENO was lower in CF compared to controls (p=0.0006) and the effect was more pronounced in CF infants without residual CFTR function (p<0.0001). This suggests that FENO is reduced in CF early in life, possibly associated with underlying CFTR dysfunction.

Elevated lung clearance index in infants with cystic fibrosis shortly after birth.

It is not known at what age lung function impairment may arise in children with cystic fibrosis (CF). We assessed lung function shortly after birth in infants with CF diagnosed by newborn screening.We performed infant lung function measurements in a prospective cohort of infants with CF and healthy controls. We assessed lung clearance index (LCI), functional residual capacity (FRC) and tidal breathing parameters. The primary outcome was prevalence and severity of abnormal lung function (±1.64 z-scores) in CF.We enrolled 53 infants with CF (mean age 7.8 weeks) and 57 controls (mean age 5.2 weeks). Compared to controls, LCI and FRC were elevated (mean difference 0.30, 95% CI 0.02-0.60; p=0.034 and 14.5 mL, 95% CI 7.7-21.3 mL; p<0.001, respectively), while ratio of time to peak tidal expiratory flow to expiratory time was decreased in infants with CF. In 22 (41.5%) infants with CF, either LCI or FRC exceeded 1.64 z-scores; three infants had both elevated LCI and FRC.Shortly after birth, abnormal lung function is prevalent in CF infants. Ventilation inhomogeneity or hyperinflation may serve as noninvasive markers to monitor CF lung disease and specific treatment effects, and could thus be used as outcome parameters for future intervention studies in this age group.

Tunable and Efficient White Light Phosphorescent Emission Based on Single Component N-Heterocyclic Carbene Platinum(II) Complexes.

A new class of cyclometalated pyridine N-heterocyclic carbene (NHC) Pt(II) complexes with electronically different alkyne derivatives (C≡CR; R = C6H4C(CH3)3 (1), C6H5 (2), C6H4F (3), C6H3(CF3)2 (4)) as ancillary ligands were synthesized, and the consequences of the electronic properties of the different substituted phenylacetylene ligands on the phosphorescent emission efficiencies were studied, where C≡CC6H4C(CH3)3 = 4-tert-butylphenylacetylene, C≡CC6H5 = phenylacetylene, C≡CC6H4F = 4-fluorophenylacetylene, and C≡CC6H3(CF3)2 = 3,5-bis(trifluoromethyl)phenylacetylene. Structural characterization, electrochemistry, and photophysical investigations were performed for all four compounds. Moreover, the emission quantum efficiencies and wavelength emission intensities of the complexes were also recorded in different weight percents in poly(methyl methacrylate) films (PMMA) and evaluated in the CIE-1931 chromaticity diagram. The square planar coordination geometry with the alkynyl ligands was corroborated for complexes 1, 2, and 3 by single crystal X-ray diffraction studies. These complexes show tunable monomeric high energy triplet emission and an additional concentration-dependent low-energy excimer-based phosphorescence. While adopting weight percent concentrations between 15 and 25%, the two emission bands covering the entire visible spectrum were obtained with these particular complexes displaying the properties of an efficient white light triplet emitter with excellent CIE-1931 coordinates (0.31, 0.33). On the basis of the high luminescent quantum efficiency of over 50% for white light emission, these compounds could be potentially useful for white organic light-emitting diodes (WOLEDs) based applications.

The immunomodulatory effect of sevoflurane in endotoxin-injured alveolar epithelial cells.

BACKGROUND: Endotoxin-induced lung injury is a useful experimental system for the characterization of immunopathologic mechanisms in acute lung injury. Although alveolar epithelial cells (AEC) are directly exposed to volatile anesthetics, there is limited information about the effect of anesthetics on these cells. In this study we investigated the effect of pretreatment with the inhaled anesthetic sevoflurane on lipopolysaccharide (LPS)-injured AEC. METHODS: AEC were incubated with 1.1 vol % sevoflurane for 0.5 h, followed by LPS stimulation for 5 h. Expression of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1beta (MIP-1beta), macrophage inflammatory protein-2 (MIP-2), cytokine-induced neutrophil chemoattractant-1 (CINC-1), and intercellular adhesion molecule-1 (ICAM-1) was analyzed. In addition, functional tests were performed through chemotaxis and adherence assays to underline the biological relevance of the findings. RESULTS: Exposure of AEC to sevoflurane resulted in a 50% downregulation of MCP-1 protein in the sevoflurane-LPS group when compared with non-sevoflurane- LPS cells (P < 0.05). MIP-1beta concentration in LPS-stimulated cells decreased by 32% with sevoflurane (P < 0.05), MIP-2 by 29% (P < 0.05), and CINC-1 by 20% (P < 0.05). ICAM-1 protein expression was attenuated by 36% (P < 0.05). This inhibition caused substantial changes in the inflammatory response of neutrophils. 33% less chemotactic activity was seen in sevoflurane-treated LPS cells (P < 0.001) as well as 47% decreased adhesion of neutrophils to AEC (P < 0.001). CONCLUSIONS: This study shows that sevoflurane alters the LPS-induced inflammatory response, not only with respect to the expression pattern of inflammatory mediators, but also regarding the biological consequences with less accumulation of effector cells such as neutrophils.

Inflammatory response of tracheobronchial epithelial cells to endotoxin.

Respiratory epithelial cells play a crucial role in the inflammatory response in endotoxin-induced lung injury, an experimental model for acute lung injury. To determine the role of epithelial cells in the upper respiratory compartment in the inflammatory response to endotoxin, we exposed tracheobronchial epithelial cells (TBEC) to lipopolysaccharide (LPS). Expression of inflammatory mediators was analyzed, and the biological implications were assessed using chemotaxis and adherence assays. Epithelial cell necrosis and apoptosis were determined to identify LPS-induced cell damage. Treatment of TBEC with LPS induced enhanced protein expression of cytokines and chemokines (increases of 235-654%, P < 0.05), with increased chemotactic activity regarding neutrophil recruitment. Expression of the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was enhanced by 52-101% (P < 0.0001). This upregulation led to increased adhesion of neutrophils, with >95% adherence to TBEC after LPS stimulation, which could be blocked by either ICAM-1 (69%) or VCAM-1 antibodies (55%) (P < 0.05). Enhanced neutrophil-induced necrosis of TBEC was observed when TBEC were exposed to LPS. Reduced neutrophil adherence by ICAM-1 or VCAM-1 antibodies resulted in significantly lower TBEC death (52 and 34%, respectively, P < 0.05). Therefore, tight adherence of neutrophils to TBEC appears to promote epithelial cell killing. In addition to indirect effector cell-induced TBEC death, direct LPS-induced cell damage was seen with increased apoptosis rate in LPS-stimulated TBEC (36% increase of caspase-3, P < 0.01). These data provide evidence that LPS induces TBEC killing in a necrosis- and apoptosis-dependent manner.

Pulmonary aspiration: new therapeutic approaches in the experimental model.

BACKGROUND: Acute lung injury caused by gastric aspiration is a frequent occurrence in unconscious patients. Acute respiratory distress syndrome in association with gastric aspiration carries a mortality of up to 30% and accounts for up to 20% of deaths associated with anesthesia. Although the clinical condition is well known, knowledge about the exact inflammatory mechanisms is still incomplete. This study was performed to define the role of alveolar macrophages in this inflammatory response. In addition, potentially modifying effects of intratracheally applied nuclear factor kappaB inhibitor pyrrolidine dithiocarbamate were investigated. METHODS: Rat alveolar macrophages were depleted by intratracheal administration of clodronate liposomes, and lung injury was evaluated 6 h after instillation of 0.1N hydrochloric acid. In a second set of experiments, pyrrolidine dithiocarbamate was intratracheally instilled 3 h after hydrochloric acid application, and injury parameters were determined. RESULTS: Depletion of alveolar macrophages resulted in decreased production of inflammatory mediators in acid aspiration (23-80% reduction of messenger RNA or protein of inflammatory mediators; P < 0.05) and consequently also in diminished neutrophil recruitment (36% fewer neutrophils; P < 0.01). Treatment with pyrrolidine dithiocarbamate was highly effective in decreasing neutrophil recruitment (66%; P < 0.01) and vascular permeability (80%; P < 0.001). CONCLUSIONS: These data suggest that alveolar macrophages play an essential role in the inflammatory response of acid-induced lung injury. For the first time, attenuation of acid-induced lung injury with an inhibitor, applied after the onset of injury, is shown.