Hypoxia-inducible factor-1 stimulates postnatal lung development but does not prevent O2-induced alveolar injury
Authors: Zhen Huang
Cameron Ackerley
Daochun Luo
Freek A Groenman
Dick Tibboel
Johan C de Jongste
Minke van Tuyl
Johanna Selvaratnam
Isabella Caniggia
Jeroen Tibboel
Irene Tseu
Jinxia Wang
Martin Post
Journal: American Journal of Respiratory Cell and Molecular Biology (2015)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: alveologenesis; bronchopulmonary dysplasia; mice; vascular development.
Affiliations: 1 Department of Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.

Abstract:  This study investigated whether hypoxia-inducible factor (HIF)-1 influences postnatal vascularization and alveologenesis in mice and whether stable (constitutive-active) HIF could prevent hyperoxia-induced lung injury. We assessed postnatal vessel and alveolar formation in transgenic mice, expressing a stable, constitutive-active, HIF1α-subunit (HIF-1αΔODD) in the distal lung epithelium. In addition, we compared lung function, histology, and morphometry of neonatal transgenic and wild-type mice subjected to hyperoxia. We found that postnatal lungs of HIF-1αΔODD mice had a greater peripheral vessel density and displayed advanced alveolarization compared with control lungs. Stable HIF-1α expression was associated with increased postnatal expression of angiogenic factors, including vascular endothelial growth factor, angiopoietins 1 and 2, Tie2, and Ephrin B2 and B4. Hyperoxia-exposed neonatal HIF-1αΔODD mice exhibited worse lung function but had similar histological and surfactant abnormalities compared with hyperoxia-exposed wild-type controls. In conclusion, expression of constitutive-active HIF-1α in the lung epithelium was associated with increased postnatal vessel growth via up-regulation of angiogenic factors. The increase in postnatal vasculature was accompanied by enhanced alveolar formation. However, stable HIF-1α expression in the distal lung did not prevent hyperoxia-induced lung injury in neonates but instead worsened lung function. 

Retracted: No

PubPeer comments:
 This paper is part of a set of 17 papers relating to the protocol approved by the ethics committee of the King Abdulaziz University (Saudi Arabia) under the **014-CEGMR-2-ETH-P**. We found some of the same authors in the 17 papers. **One protocol approved by the ethic committee under the number 014-CEGMR-2-ETH-P:** Authors mentioned in each paper that the study has been approved by the ethics committee of the King Abdulaziz University (Saudi Arabia) under the number 014-CEGMR-2-ETH-P. Considering an ethics approval number is related to one protocol only, readers could consider the 17 papers are related to the same protocol. **Discrepancies regarding the ethical reason justifying the recruitment of males only** In 6 articles, only one single male participant have been recruited. In one article (see article #5), the authors mention that: * For ethical reasons, all individuals from Saudi Arabia were male *. This mention is really surprising considering the other 10 papers with the same ethical approval number from the same ethical committee describe studies -tOn men and women. -tOr on 1 woman only. Could the authors explain why they have mentioned for article #5 all individuals from Saudi Arabia were male for ethical reason? Especially considering in other papers, the same authors describes that the protocol with the number 014-CEGMR-2-ETH-P have recruited male and women. **Participants and recruitment periods** In the 17 papers, authors mentions that the recruitment has been done on: -tHealthy participants -tAnd or Volunteers with obesity. In 6 papers, the authors mention that the study recruited between 28 and 117 participants depending on the paper. Among these 6 papers, the recruitment period is also different in each paper: -t4 don t provide the recruitment dates. -t1 paper describes a period of recruitment between January 2015 and December 2015 -t1 paper describes a period of recruitment between September 2015 and March 2016 In the other 11 papers, each paper describes a study on only one single participant: -t4 articles describe a study on a 24 year-old male in April 2013 (articles #14, #15, #16, #17) -t1 article describes a study on a 42 years-old women the 24 may 2014 (article #9) -t4 articles describe a study on a 50 years-old women in 2016 (articles #1, #3, #4, #6) -t2 articles describe a study on a 25 years-old male (articles #10 and #13). No data on the recruitment date. Readers could note that the recruitment dates of the studies on a single participant in 2013 and 2014 don t match with the studies on dozens or hundreds of participants recruited in 2015 and 2016. **Monkeys are used in one paper** In one paper, Authors mention that they assessed the gut microbiome and dietary patterns by comparing healthy volunteers and Monkeys population. **Different types of samples** -t1 paper describes a study which collects blood samples only -tThe other papers describe studies which collect stool samples only. **In France, only certified IRB (Comitu00e9 de Protection des Personnes) are qualified to approve prospective study in humans.** 2 papers describes studies performed in two or more countries and including French participants (articles #7 and #8). These papers describes an approval from the IFR48 ethics committee. In accordance with French law, only a certified IRB can approve research in human. Approval from the certified IRB must be obtained before to recruit participants The IFR48 ethics committee is not on the list of the certified IRB in France and don t have the ability to validate a prospective study in human, especially in healthy volunteers. In accordance with Helsinki Declaration and Editors guidances, a clinical research must be approved according to the relevant laws of the countries of the participants. The Editors should clarify this point and ensure that an approval from the Comitu00e9 de Protection des Personnes has been obtained for this protocol, especially considering the recruitment of health volunteers. The date of the approval, the scope of the protocol and the recruitment dates of participants should be clarified for every paper. **Different types of objectives** The 11 papers related to the studies on single participants are intended to describe 1 new bacteria per paper. The 6 other papers describes different types of objectives: -tDiet influence on some blood values -tComparison on the gut microbia in different countries -tComparison of Treponema species between rural and urban population -tImpact of smoking cessation, coffee and bread consumption on the intestinal microbial composition -tGut microbiome and dietary patterns **How the same protocol can cover so many different interventions, different study designs and different types of participants?** Could the authors disclose the protocol of the study 014-CEGMR-2-ETH-P? Or, at least, explain how a unique protocol can cover the diversity of situations described by the 17 papers ? How the same protocol can recruit one single participant in 2013 to describe new bacteria in stools and then start a recruitment of hundreds of participants 2 years later? Or doing another study by adding a population of monkeys in the same protocol ? The Editors should also clarify how the same protocol can cover so many different type of study design, inclusion criteria and exclusion criteria. Could the authors details the ethical approval process and the dates of the ethics approval ? **Salami publication** According to the article  [Salami publication: definitions and examples]  : * Salami publication can be roughly defined as a publication of two or more articles derived from a single study. Articles of such type report on data collected from a single study split into several segments just large enough to gain reasonable results and conclusions, also known as  minimal publishable unit .* (...) * From the publication ethics point of view, it gives undeserved credit to authors, misleads the scientific community and directly influences clinical practice by distorting medical evidence. * **LIST OF THE 17 PAPERS COVERED BY THE SAME ETHICS APPROVAL NUMBER 014-CEGMR-2-ETH-P IN SAUDI ARABIA** 1.t[Current microbiology - Anaerococcus jeddahensis sp. nov., a New Bacterial Species Isolated From Healthy Nomadic Bedouin Woman From Saudi Arabia] 2.t[JPMA - Diet influences levels of plasma lipopolysaccharide [LPS] and its soluble receptor [sCD14] in Saudis] 3.t[New microbes and new infections - Taxono-genomics and description of Gordonibacter massiliensis sp. nov., a new bacterium isolated from stool of healthy patient] 4.t[New microbes and new infections - Description of u2018Arabia massiliensisu2019 gen. nov., sp. nov.,u2018Gordonibacter massiliensisu2019 sp. nov., and u2018Bacilliculturomica massiliensisu2019 gen. nov., sp. nov., isolated from a faecal specimen of a 50-year-old Saudi Bedouin woman] 5.t[New microbes and new infections - Comparison of the gut microbiota of obese individuals from different geographic origins] 6.t[New microbes and new infections - u2018Beduinella massiliensisu2019, gen. nov., sp. nov. a new genus representing a new family in the phylum Firmicutes, and proposal of Beduinellaceae fam. nov.] 7.t[New microbes and new infections - Treponema species enrich the gut microbiota of traditional rural populations but are absent from urban individuals] 8.t[Nutrition diabetes - Comparison of the gut microbiota of people in France and Saudi Arabia] 9.t[Omics: a journal of integrative biology - Rise of Microbial Culturomics: Noncontiguous Finished Genome Sequence and Description of Beduini massiliensis gen. nov., sp. nov.] 10.t[Omics: a journal of integrative biology - Microbial Culturomics to Map Halophilic Bacterium in Human Gut: Genome Sequence and Description of Oceanobacillus jeddahense sp. nov.] 11.t[PloS one - Impact of smoking cessation, coffee and bread consumption on the intestinal microbial composition among Saudis: A cross-sectional study] 12.t[Scientific reports - Gut microbiome and dietary patterns in different Saudi populations and monkeys] 13.t[Standards in genomic sciences - Genome sequence of Oceanobacillus picturae strain S1, an halophilic bacterium first isolated in human gut] 14.t[Standards in genomic sciences - Non-contiguous finished genome sequence and description of Clostridium saudii sp. nov] 15.t[Standards in Genomic Sciences - Non-contiguous finished genome sequence and description of Corynebacterium jeddahense sp. nov.] 16.t[Standards in genomic sciences - Non contiguous-finished genome sequence and description of Bacillus jeddahensis sp. nov.] 17.t[Standards in genomic sciences - Non contiguous-finished genome sequence and description of Clostridium jeddahense sp. nov.] ,