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From the authors

K. Woyda, R. T. Schermuly
European Respiratory Journal 2009 33: 1237; DOI: 10.1183/09031936.00012909
K. Woyda
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R. T. Schermuly
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We would like to thank C. Méhats and colleagues for their comments regarding our paper on phosphodiesterase (PDE)4 inhibition in hyperoxia-induced bronchopulmonary dysplasia (BPD) 1. In our article, we stated that inhibition of PDE4 with cilomilast leads to an improved alveolarisation in hyperoxia-induced lung injury in mice 1. C. Méhats and colleagues raised concerns about our study design and the obtained results. We would like to respond to the issues in question.

The first point of criticism addresses differences regarding the therapeutic impact of the PDE4 inhibitor cilomilast in our study of mice, as compared to rolipram in the study of MÉhats et al. 2, which was conducted on rats. MÉhats et al. 2 demonstrated that treatment of hyperoxia-exposed rats with 0.5 mg·kg−1·day−1 rolipram prolonged the survival of the treated rats significantly but could not improve alveolarisation. Further doses of rolipram slowed the growth of the treated hyperoxic and normoxic rat pups compared to the untreated hyperoxic group. In contrast, de Visser et al. 3 reported improved histopathology in terms of thinning of septa and a reduction of inflammation and oedema after PDE4 inhibition with rolipram and piclamilast. Interestingly, de Visser et al. 3 did not note adverse effects on the body weight with a dose of 125 μg·kg−1·day−1 rolipram and were able to prolong the median survival by 3 days. In our study, mice were used instead of rats. In addition, the animals in our study were exposed to lower oxygen concentrations (85% O2) as compared to those used in the study of MÉhats et al. 2 (95% O2). Extremely high levels of O2 are known to induce oedema formation, inflammation, and high mortality in rats, thus mimicking acute lung injury rather than an arrest in lung alveolarisation. Slightly lower O2 levels as used in our study, however, appear to be better suited to the investigation of BPD-like events, as characterised by increased medial wall thickness and thinning of septa. In addition, no side-effects on food intake were observed in the animals treated with cilomilast. On the contrary, the treated hyperoxic mice even showed a slight improvement in body weight as opposed to hyperoxic controls. Of course, the issue of nutrition is important in this regard, as described in studies from Massaro et al. 4, who showed that proper feeding has a direct impact on murine alveolar regeneration.

C. Méhats and colleagues claim that the conclusion of our study regarding a potential impact of cilomilast for the treatment of BPD is overstated. They refer to the minor degree of changes in the histopathological parameters and a lack of biological effects that can be related to these changes. It is possible that C. Méhats and colleagues have misinterpreted figure 9 of our paper 1, which clearly shows that dynamic compliance is significantly reduced in hyperoxic mice (as compared to controls). This proves that treatment with cilomilast significantly and expediently restores this functional parameter (with compliance values even slightly above control levels).

Another point of criticism refers to the morphometric methodology used in our study. The customised Leica Q Win analysing software (Leica Microsystems GmbH, Wetzlar, Germany) can be regarded as a reliable tool for accurate quantification of alveolar structures in an investigator-independent manner 5–8. When establishing this methodology in our laboratory, of course, validations were undertaken by comparison to standard techniques, revealing a high accuracy of the automatised technique. In addition, inter-observer variability is avoided by this software-based method as opposed to the standard point-counting method.

Finally, it has to be kept in mind that compounds like rolipram belong to the first generation of PDE4 inhibitors and their clinical utility is limited by several side-effects, including nausea, emesis and gastric acid secretion. In contrast, the second generation of PDE4 inhibitors offer an improved side-effect profile and cilomilast is already approved for treatment of chronic obstructive pulmonary disease.

In conclusion, we think that based on the above listed facts, it is appropriate to say that cilomilast has potential beneficial effects in bronchopulmonary dysplasia.

Statement of interest

None declared.

    • © ERS Journals Ltd

    References

    1. ↵
      Woyda K, Koebrich S, Reiss I, et al. Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia. Eur Respir J 2009;33:861–870.
      OpenUrlAbstract/FREE Full Text
    2. ↵
      Méhats C, Franco-Montoya ML, Boucherat O, et al. Effects of phosphodiesterase 4 inhibition on alveolarization and hyperoxia toxicity in newborn rats. PLoS ONE 2008;3:e3445
      OpenUrlCrossRefPubMed
    3. ↵
      de Visser YP, Walther FJ, Laghmani EH, van WS, Nieuwland K, Wagenaar GT. Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury. Eur Respir J 2008;31:633–644.
      OpenUrlAbstract/FREE Full Text
    4. ↵
      Massaro D, Alexander E, Reiland K, Hoffman EP, Massaro GD, Clerch LB. Rapid onset of gene expression in lung, supportive of formation of alveolar septa, induced by refeeding mice after calorie restriction. Am J Physiol Lung Cell Mol Physiol 2007;292:L1313–L1326.
      OpenUrlAbstract/FREE Full Text
    5. ↵
      Bonniaud P, Kolb M, Galt T, et al. Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis. J Immunol 2004;173:2099–2108.
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    6. Goldstein I, Bughalo MT, Marquette CH, Lenaour G, Lu Q, Rouby JJ. Mechanical ventilation-induced air-space enlargement during experimental pneumonia in piglets. Am J Respir Crit Care Med 2001;163:958–964.
      OpenUrlPubMedWeb of Science
    7. Peces-Barba G, Ruiz-Cabello J, Cremillieux Y, et al. Helium-3 MRI diffusion coefficient: correlation to morphometry in a model of mild emphysema. Eur Respir J 2003;22:14–19.
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      Rubio ML, Martin-Mosquero MC, Ortega M, Peces-Barba G, Gonzalez-Mangado N. Oral N-acetylcysteine attenuates elastase-induced pulmonary emphysema in rats. Chest 2004;125:1500–1506.
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    European Respiratory Journal May 2009, 33 (5) 1237; DOI: 10.1183/09031936.00012909

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