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The role of inflammatory cell infiltration in the development of hyperresponsiveness of the airways to muscarinic challenge remains poorly understood. Unlike previous investigations that only examined conducting airway inflammation, the present study utilized both bronchoalveolar lavage (BAL) and lung tissue digestion to determine rat lung inflammatory cell contents following a 4-h exposure to 2 ppm ozone. Immediately following ozone exposure, neutrophil content of the lung tissue was significantly increased and reached a value that was fourfold higher than air-exposed controls by 3 h postexposure. Although lavage-recovered neutrophils were elevated at 24 h, tissue neutrophil numbers had returned to control values. This transient elevation of tissue neutrophils directly correlated with an elevation and subsequent decline of airway hyperresponsiveness, measured as a decrease in the intravenous dose of methacholine provoking a 200% increase in airway resistance (PD(200)R). Animals rendered neutropenic with a rabbit anti-rat neutrophil serum prior to exposure were protected from ozone-induced hyperresponsive airways, further demonstrating an association between neutrophil infiltration into the lung and altered airway physiology. Although BAL-recovered neutrophils demonstrated no adverse effects as a result of ozone exposure, macrophages were not only found to be necrotic but also displayed altered oxidative metabolism when challenged with phorbol myristate acetate. Thus, changes in the microenvironment of the airways smooth muscle were shown to be associated with transient accumulation of neutrophils within the lung tissue and abnormalities of bronchoalveolar lavage-recovered macrophages.

Identifying whether or not neutrophils have a role to play in the early stages of acute lung epithelial injury brought about by inhalation of reactive substances continues to be a major area of investigation. In this study, the availability of circulating neutrophils was manipulated by treatment with either cyclophosphamide or rabbit antiserum against rat neutrophils, prior to exposures to air, a single high ozone exposure of 1 or 2 ppm for 3 h, or a continuous exposure to 0.8-1.0 ppm for up to 48 h. Although cyclophosphamide treatment resulted in undetectable levels of neutrophils in the blood, the recovery of tissue marginated-interstitial neutrophils of 1 x 10(6) cells by collagenase tissue digestion was not significantly diminished at the onset of air and ozone exposures. Cyclophosphamide treatment alone did not cause any permeability damage to air-exposed rat lungs, but did ameliorate ozone-induced increases in bronchoalveolar lavage (BAL) neutrophil and albumin recoveries after both short-term and 1 d of continuous ozone exposure. In contrast to cyclophosphamide, antiserum treatment resulted in greater than a 90% decrease in neutrophil recoveries from both blood and lung tissue at the onset of air and ozone exposures. Antiserum treatment also abrogated ozone-induced neutrophil accumulations in lung lavageable spaces following both single and continuous ozone exposures, but did not significantly affect ozone-associated lung permeability damage indicated by unaltered BAL fluid albumin recoveries. These data demonstrated that under experimental conditions when neutrophils remain within lung tissue marginated and interstitial pools, reduction in circulating blood neutrophil availability is associated with a concomitant decrease in ozone-induced lung damage.

Objectives Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS). Methods This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval (‘70% fT>MIC’)] and to investigate the tolerance and safety in neonates. Results A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7–41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3–41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin. Conclusions Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.

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