Respiratory Research - Latest Comments

Adding a sentence to the bottom of the table 1.

Lunyin Yu — 2011-12-15T12:56:32Z

Adding the following to the bottom of the table 1. BMC = transplantation of bone marrow cells without shRNA, BMC+S-R = transplantation of bone marrow cells with scrambled shRNA, BMC+ CXCR4 = transplantation of bone marrow cells with CXCR4 shRNA.

efficient wording

JULIA PETEET — 2011-10-12T11:41:41Z

I believe the article would be improved if the authors would substitute Group 1 and Group 2 for: "... ([less than or equal to]50 years old and [greater than or equal to]52 years old..." after initially stating the criteria for each group.

The differential role of mitochondria in asthmatic lung

Ulaganathan Mabalirajan — 2010-09-07T14:21:21Z

This study revealed novel and interesting findings, such as glycolysis and calcium binding in asthmatic early airway response (EAR) in murine OVA model. In addition, they found increased biological activity of mitochondria in asthmatic mice lung during EAR. However, we think that interpretation and discussion related to the mitochondria needs some caution, update and a holistic view.
Asthma is a heterogeneous disease and various immune cells and structural cells participate in its pathophysiology. Recent literature has highlighted the importance of mitochondria in asthma pathogenesis. A common finding in asthma is epithelial injury and apoptosis associated with high levels of oxo-nitrosative stress. Mitochondrial dysfunction contributes importantly to this process, leading to large production of reactive oxygen species (ROS), which in the presence of disordered nitric oxide metabolism further leads to generation of reactive nitrogen species. It has been shown that coenzyme Q and vitamin E which are mitochondrial target antioxidants and esculetin have beneficial effects in asthma with reduction in mitochondrial dysfunction [1-3]. Due to the heterogeneous nature of asthma, multifunctionality of mitochondria and cell-lineage specific effects, the exact role of mitochondria in asthma pathogenesis is not clear. Current literature revealed that mitochondria seem to have differential roles in asthmatic lungs.
Increased glycolysis may accompany reduced mitochondrial electron chain activity in the context of hypoxic response activation by hypoxia inducible factor-1 [5]. This preserves the integrity of the electron transfer chain during conditions of increased electron accumulation and ROS generation from complex III. Interestingly, such hypoxic response can be triggered by fall in available oxygen to complex IV as well as any other factor(s) that increased ROS generation. It is noteworthy that mitochondrial ROS increase the secretion of proinflammatory mediators such as histamine and serotonin from mast cell to initiate EAR [6]. In addition, it seems that mitochondrial dysfunction activates adoptive immune response by inducing IL-4 production [6]. In this context, we found that neutralizing IL-4 ameliorated the mitochondrial dysfunction along with the restoration of mitochondrial ultrastructural changes in bronchial epithelia [7] in OVA murine model of asthma. In support of this view, underlying mitochondrial dysfunction in airway epithelium of ragweed allergen sensitized mice aggravated the features of asthma such as bronchial hyperresponsiveness [8]. In contrast to these findings of mitochondrial dysfunction in mast cells and bronchial epithelia, increased mitochondrial activity and mitochondrial biogenesis have been observed in asthmatic airway smooth muscle and it has been suggested that these are crucial in smooth muscle hypertrophy of airway remodeling [9]. In addition, modulation of mitochondrial function may delay apoptosis of immune cells such as eosinophils and neutrophils [10].
In summary, mitochondrial function seems to be differentially altered in different cell types of asthmatic lungs and this may vary depending on the natural evolution of asthma pathology. Therefore, careful investigations are required to dissect the exact role of mitochondria in cell specific manner for asthma pathogenesis.

Sincerely,
Ulaganathan Mabalirajan MBBS, PhD
Amit Kumar Dinda, MD, PhD
Anurag Agrawal MD, PhD
Balaram Ghosh PhD, FNASc, FASc

Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung disease, Institute of Genomics and Integrative Biology, India (UM, AA and BG), and Department of Pathology, All India Institute of Medical Sciences, India (AKD).

References

1. Gvozdjáková A, Kucharská J, Bartkovjaková M, Gazdíková K, Gazdík FE: Coenzyme Q10 supplementation reduces corticosteroids dosage in patients with bronchial asthma. Biofactors 2005, 25:235-240.
2. Mabalirajan U, Dinda AK, Sharma SK, Ghosh B: Esculetin restores mitochondrial dysfunction and reduces allergic asthma features in experimental murine model. J Immunol 2009, 183: 2059-2067.
3. Mabalirajan U, Aich J, Sharma SK, Ghosh B: Effects of vitamin E on mitochondrial dysfunction and asthma features in an experimental allergic murine model. J Appl Physiol 2009, 107:1285-1292.
4. Xu YD, Cui JM, Wang Y, Yin LM, Gao CK, Liu YY, Yang YQ: The early asthmatic response is associated with glycolysis, calcium binding and mitochondria activity as revealed by proteomic analysis in rats. Respir Res 2010, 11:107.
5. Semenza GL: Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda) 2004, 19:176-82.
6. Chodaczek G, Bacsi A, Dharajiya N, Sur S, Hazra TK, Boldogh I: Ragweed pollen-mediated IgE-independent release of biogenic amines from mast cells via induction of mitochondrial dysfunction. Mol Immunol 2009, 46:2505-2514.
7. Mabalirajan U, Dinda AK, Kumar S, Roshan R, Gupta P, Sharma SK, Ghosh B: Mitochondrial structural changes and dysfunction are associated with experimental allergic asthma. J Immunol 2008, 181: 3540-3548.
8. Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I: Mitochondrial dysfunction increases allergic airway inflammation. J Immunol 2009, 183:5379-5387.
9. Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, Berger P: Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med 2007, 204:3173-3181.
10. Dewson G, Cohen GM, Wardlaw AJ: Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils. Blood 2001, 98:2239-2247.

Circulating endothelial precursors and the hypoxia machinery. Reply to comments

Michele Ciulla — 2008-03-04T17:38:19Z

Respiratory Research

Reply to comments December 24, 2007

Dear Dr Prakash,

Thank you for you interest in our paper that we believe that is the first linking in healthy subjects a simulated altitude [1] with the circulating endothelial precursors and the hypoxia machinery.Your comments give us the opportunity to clarify some aspects.

1. In our study we measured the SpotOxygen Saturation of haemoglobin(SpO2)by using a pulseoximeter. Pulseoximetry is the most convenient non-invasive method of monitoring arterial saturation continuously. Although there are many advantages of using pulse oximetry as a tool for monitoring oxygen saturation in arterial blood, there are also potential pitfalls.The pulsatile component of the signal represents the arterial absorption and forms only a small proportion of the total, the signal is thus very susceptible to noise, for example in association to movements and during fluctuations in ambient light that can produce false pulsatile signals; also carboxyhaemoglobin causes misreadings the pulsatile oximeter to overread. Furthermore, no absolute method for calibrating pulseoximeters yet exists, and manufacturers make use of specific equations obtained by comparing wavelength measurement with arterial blood samples from volunteers [2]. Nonetheless the measurement of the peripheral oxygen saturation of haemoglobin is considered a standard, therefore the SpO2 measurements we reported are affordable. The Alveolar Oxygen Partial Pressure(PAO2) values were measured by using a gasanalyzer, estimated indirectly by using the following equation:

PAO2=FiO2*(BP-47)-PaCO2/R

where: - FiO2 is the inhaled Fraction of oxygen- BP is the barometric pressure - PaCO2 is the arterial pressure of CO2 (derived from another formula) - R is the respiratory exchange rate. As you can see 47 is the pH2O that is considered as a constant in the formula, while both the hypoxicator and the gasanalyzer dried the air out during the test, so the volunteers breathed a low pH2O air. If you consider this and correct the formula with the pH2O value of 36, you obtain the data shown in table 1. Since hypoxia was applied to all subjects in the same experimental conditions of pH2O, in the table reported in the paper we preferred to show the data as calculated by the gasanalyzer, without changing the original equation. Therefore the PAO2 values accounting for a different pH2O could be derived simply by introducing a correction factor in the original equation.

2. The t-test is a useful tool for comparing the means of two groups; in our study we used the ANOVA test that is indicated when comparing 3 or more groups; furthermore, our samples are PAIRED, this fact means that individual values (same subjects) obtained before and after the test are compared; comparison of the means is not allowed in this model but only for UNPAIRED samples.

3. We agree that an arterial blood sample would have been useful but this procedure was not justified in healthy volunteers (students). Finally, many thanks to BMCO penAccess model that allows all researchers to discuss on-line their results.

References

1.Ciulla MM, et al.: Effects of simulated altitude (normobarichypoxia) on cardiorespiratory parameters and circulating endothelial precursors in healthy subjects. Respir Res 2007; 8:58.

2. Hutton P, Clutton-Brock T: The benefits and pitfalls of pulse oximetry. BMJ 1993, 307:457-458.

atmospheric air (baseline)

gas - P(mmHg) - Dry-fraction

O2 - 160 - 0,21

CO2 - 0 - 0

N2 - 588 - 0,79

H2O - 12 - 0

atmospheric air (hypoxia)

gas - P(mmHg) - Dry-fraction

O2 - 80 - 0,12

CO2 - 0 - 0

N2 - 672 - 0,88

H2O - 8 - 0

t0 alveolar air

gas - P(mmHg)

O2 - 100

CO2 - 40

N2 - 573

H2O - 47

Tot 760

t0-t1 alveolar air

gas - P(mmHg)

O2 - 52

CO2 - 40

N2 - 632

H2O - 36

Tot 760

Re: Effects of normobaric hypoxia on cardiorespiratory parameters and endothelial progenitor cells in peripheral blood in healthy subjects

E Sankaranarayanan Prakash — 2007-11-14T17:52:15Z

Ciulla et al are complemented for their investigation of an important research question.

From data in Table 1, it is seen that oxygen saturation of hemoglobin is as high as 86.8% (mean value) when alveolar PO2 is as low as 30 mm Hg. Typically, the oxygen saturation of Hb A is expected to be as low as 50% when the arterial PO2 is 30 mm Hg [1]. Were the PAO2 values directly estimated by sampling end tidal alveolar gas? Or were they calculated from the alveolar gas equation? Anyway PaCO2 has not been estimated.

In Table 1 (on page 17 of the PDF version), it is mentioned that the concentration of endothelial precursor cells has increased from 0.38 +/- 0.56; [mean (SD)] to 0.65 +/-0.72 cells per microliter. The P value for this difference is noted as 0.016. From calculating a P value with just the mean and SD, for a sample size of 8, I got a P value of 0.42.

The increase in minute ventilation in response to hypoxemia is insignificant although this may be attributable to the fall in PaCO2 and rise in pH of blood. In this context, it would have been useful to have a sample of arterial blood sampled at the end of 1 hour of normobaric hypoxia.

References:

[1] Ciulla MM et al. Effects of simulated altitude (normobaric hypoxia) on cardiorespiratory

parameters and circulating endothelial precursors in healthy subjects. Respiratory Research 2007, 8:58; doi:10.1186/1465-9921-8-58

[2] Ganong WF. Review of Medical Physiology, International Edition, 2005, Mc Graw Hill Co., figure 35-2 in p. 667.

Re: Pre-natal and post-natal exposure to respiratory infection and atopic diseases development: a historical cohort study.

Roos Maria Desirée Bernsen — 2006-07-06T09:49:46Z

We read the interesting study by Zutavern et al (1), approaching the problem of assessing the relationship between (exposure to) infections and allergic diseases in an original way by using population level data as a proxy for individual exposure. Exposure between the start of pregnancy and the first birthday was defined as a high incidence of acute respiratory infections in that period in the region (as reported by physicians to the surveillance system in the former German Democratic Republic). The study population included children (aged 5-14 years) born between 1977 and 1990 in three different regions in the former German Democratic Republic and was assessed between 1992 and 1999.

We think, however, that the authors have overlooked an important confounder when adjusting the relationship between exposure and allergic disease, i.e. year of assessment. For already some five years after the re-unification in 1990 there was an important increase in the prevalence of hay fever and atopic sensitization (2).

A second point is that they considered the number of siblings (or rather family size as a proxy variable) as a possible confounder, but the number of older siblings would have been more appropriate as the time frame under study was pregnancy and first year of life.

References

1. Zutavern A, von Klot S, Gehring U, Krauss-Etschmann S, Heinrich J: Pre-natal and post-natal exposure to respiratory infection and atopic diseases development: a historical cohort study. Respiratory Research 2006, 7:81.

2. von Mutius E, Weiland SK, Fritzsch C, Duhme H, Keil U: Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany. Lancet 1998;351:862-6.

Roos M.D. Bernsen PhD(1)

Johannes C. van der Wouden PhD(2)

1. United Arab Emirates University

Al Ain

United Arab Emirates

Department of Community Medicine

2. Erasmus MC – University Medical Center Rotterdam

The Netherlands

Department of General Practice

E-mail: j.vanderwouden@erasmusmc.nl

adjuvanted vaccines for bird flu counterindicated?

Mary Quijano — 2005-11-26T04:09:49Z

Recent research data suggests that the lethality of the H5N1 strain of avian influenza among young healthy adults may be due to its stimulation of an excessive immune response in the epithelial cells of the respiratory system. If this proves to be true, then might it not be counterindicated to provide a lower dose of flu vaccine with adjuvants to stimulate the immune system, as WHO has been proposing to the laboratories producing the vaccines as a solution to inadeqate supplies? The research paper suggests immune suppressors as a possible life saving treatment to those infected with the virus, therefore it would seem stimulating a stronger immune response with adjuvants might be a wrong approach.

Correction to Initials on Authors List

W. Alan Mutch — 2004-11-25T22:04:45Z

Could you please correct the initials of one of the authors on the web site and on the abstract to agree with the correct initials on the paper.

It should read E. K-Y. Walker.

Thank you for attention to this request.

Competing Interest Statement

W. Alan Mutch — 2004-11-24T22:51:34Z

See below.