Does air pollution exacerbate asthma?

A 2007 article in the Annals of Allergy, Asthma & Immunology asked the very salient question: does air pollution exacerbate asthma?

The objective of the article was to investigate associations between traffic and outdoor air pollution levels near residences and poorly controlled asthma among adults diagnosed as having asthma in Los Angeles and San Diego counties.

The authors estimated traffic density (TD) within 500 feet of 2001 California Health Interview Survey (CHIS) respondents' reported residential cross-street intersections. They then assigned annual average concentrations at government monitoring stations within a 5 mile radius of reported residential cross-street intersections of:

1. ozone

2. nitrogen dioxide

3. particulate matter (PM) 2.5 and 10 micrometers or less in diameter

4. carbon monoxide

In order to obtain the study population, 19,664 individuals were interviewed; 2,237 (11.4%) were diagnosed by a physician as having asthma. These individuals’ residence locations were entered into a database. The final study population was 1,609 adults (others were excluded because of missing data).

Exposure evaluation was evaluated by examining traffic density, which was based on a 500 foot buffer around person's probable home street segment. From the nearest measuring station within 5 miles of the respondent, the authors determined annual average concentrations of: ozone, nitrogen dioxide, particulate matter 2.5 micrometers or less or 10 micrometers or less, carbon monoxide.

For the statistical analysis, traffic density was divided into three tiers:

1. Low TD (20th percentile or less)

2. Medium TD (21-80 percentil)

3. High TD (> 80th percentile)

The results can be summarized in the following 4 main points:

1. There was a 2-fold increase in poorly controlled asthma among asthmatic adults (OR 2.11, 95% CI 1.38-3.23) in the highest quintile of traffic density after adjusting for age, sex, race, and poverty.

2. Similar increases were seen for nonelderly adults, men, and women. The strongest associations were seen in elderly adults (OR 3, 95% CI 1.13-7.91).

3. Ozone exposures were associated with poorly controlled asthma among two subgroups:

- elderly adults (OR 1.7, CI 0.91-3.18 per 1 pphm)

- men (OR 1.76, CI 1.05-2.94 per 1 pphm)

4. Particulate matter 10 micrometers or less affected primarily women (OR 2.06, CI 1.17-3.61), even at levels below national air quality standard.

The authors’ conclusion? Heavy traffic and high air pollution levels near residences are associated with poorly controlled asthma.

While this may seem like a relatively straightforward conclusion based on the data, this study had some very significant caveats to keep in mind:

1. Misclassification of exposures from stations:

- Traffic pollutants can have a strong spatial gradient, meaning levels detected at measuring stations might not reflect actual exposure levels of individuals.

2. Resident variability:

- The study did not take into account variables such as personal mobility, occupation-related exposures, or indoor exposures.

3. Temporal ambiguity

- This study was based on cross-sectional survey data, so the length of time any individual lived in a neighborhood was unknown.

4. Medication use

- Individuals’ use of medications was unknown; use could reduce symptoms and lead to underestimated prevalence of poorly controlled asthma.

Y-Y Meng, et al. Traffic and outdoor air pollution levels near residences and poorly controlled asthma in adults. Annals of Allergy, Asthma, & Immunology 2007;98:455-463.

Novel NF-Kb links inflammation and cancer promotion

A recent paper by researchers at the University of California [1] reveals a novel mechanism by which chronic inflammation may play a decisive role in the promotion of cancer. This mechanism is a sort of molecular “cross-talk” between two processes in cells which were thought to be distinct – cell development and inflammation. This cross-talk comes through the actions of a protein, p100, which has been found to be crucial in a cell’s normal developmental metabolic pathways as well as in the cell’s response to inflammation. Novel cancer therapeutic treatments which target developmental pathways linked to chronic inflammation via p100 may prove effective in conjunction with the use of current anti-inflammatories such as NSAIDS.

NF-κB activity is inducible by a diverse range of stimuli including pathogen derived substances and intercellular mediators of inflammation. It is known that NF-κB is normally repressed by three different intracellular inhibitors (IκB-a,b,e proteins),and that during classical inflammatory signaling these inhibitors are released from binding NF-κB, resulting in its activation. A second, independent NF-κB activation pathway is thought to be activated in response to cell developmental signals rather than inflammatory signals. The molecular mechanism of this particular pathway has remained uncertain, but the results of this study show that a fourth IκB inhibitor (p100) is involved in the activation of NF-κB in developmental pathway signaling, such as during lymphoid organogenesis (see included figure).

This diagram reveals the cross-talk between NF-κB activation via inflammatory or developmental signaling – inflammatory signaling can activate developmental (cell reproduction and differentiation) pathways to some extent and vice-verse. And further work by the researchers showed that the “cross-activation” of developmental pathways by classical inflammatory signaling was much stronger, and of longer duration, than the normal developmental activation signal strength. For example, a 1 hr pulse of TNF-a stimulation resulted in an elevation of p100 protein of about 4-fold, that persisted for more than 20 hr. Remarkably, the researchers also showed that the strength of this cross-talk increased with repeated signaling – in other words, the longer cells were exposed to inflammatory signals via TNF-a, the more they were stimulated to reproduce! This is in marked contrast to the normally accepted role of TNF-a in signaling cell death.

The researchers speculate that in epithelial cells that are exposed to prolonged periods of inflammation, such as they might experience during chronic inflammatory diseases, the amount of cross-talk between the classic TNF-a mediated inflammatory cell death pathway and the p100 mediated developmental cell growth pathway may profoundly shift, with the inflammatory signals generating a stronger and stronger cell growth signal in place of the expected cell death signal. This could be the mechanism responsible for chronic inflammations being able to promote the growth of many types of cancers – after prolonged exposure, inflammatory TNF-a signals that were originally responsible for inducing cell death (and resolving inflammation and tissue repair processes) become instead growth stimulating signals that drive epithelial cells toward unrestrained cancerous growth.


1. Basak S, Kim H, Kearns JD, Tergaonkar V, O'Dea E, Werner SL, Benedict CA, Ware CF, Ghosh G, Verma IM, Hoffmann A.(2007) A fourth IkappaB protein within the NF-kappaB signaling module. Cell. Vol 128(2) p369-81.

NSAIDS and Cancer Prevention

Over the last four decades dozens of epidemiological, clinical and experimental studies have established nonsteroidal anti-inflammatory drugs (NSAIDs) as promising epithelial cancer chemopreventive agents. The long-term use of aspirin and other NSAIDs has been shown to reduce the risk of cancer of the colon and other gastrointestinal organs, as well as cancer of the breast, prostate, lung, and skin. In a recent review, Harris[1] et. al. comprehensively reviewed the published research on NSAIDs and cancer incident. Data from 91 epidemiologic studies were analyzed for the dose response of relative cancer risk and level of NSAID intake for ten prevalent human cancers. The results showed a significant exponential decline in the risk with increasing intake of NSAIDs (primarily aspirin or ibuprofen) for 7 out of the 10 cancers, including the four major types: colon, breast, lung, and prostate cancer. Consistent daily intake of NSAIDs (primarily aspirin), produced risk reductions of 73% for stomach, 69% for esophageal, 63% for colon, 47% for ovarian, 39% for breast and prostate, and 36% for lung! NSAID effects became apparent after five or more years of use and were stronger with longer duration.

Despite general consensus as to the effectiveness of NSAIDs for cancer prevention, unresolved questions with regard to safety, efficacy, optimal treatment regimen, and mechanism of action currently limit the clinical application of NSAIDs to the prevention of cancer. Also, the development of safe and effective NSAIDs for chemoprevention is complicated by the potential that rare, serious toxicity may offset the benefit of treatment with these drugs given to healthy individuals who have a low risk of developing cancer. However, I believe there is growing support for the view that a full understanding of the role of NSAIDs in the prevention and treatment of epithelial cancers will be an integral part of the development of effective future treatments for reducing mortality and morbidity from most cancers.


1. Harris RE, Beebe-Donk J, Doss H, Burr Doss D. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep. 2005 Apr;13(4):559-83.

Chronic Beryllium Disease --going beyond HLA-DPB1?

I have been working for several years with a doctor who does research with chronic beryllium disease (CBD). If you recall from our notes, this is a disease which is caused by inhalation of beryllium dust and an immune response which leads to granuloma formation in the lung. There is a known association between certain HLA-DPB1 alleles and CBD and we are always looking for ways to better understand what this means. The article “Electrostatic Potential on Human Leukocyte Antigen: Implications for Putative Mechanism and Chronic Beryllium Disease” describes how the authors constructed structural models of HLA-DP representing several distinct allotypes and how they calculated the electrostatic potential on the surface of these models. They determine that the higher the negative charge for the HLA-DPB1 alleles the more likely that the person would have chronic beryllium disease. These charges are then related back to certain alleles. I guess I have a question for anyone who may be reading this: Does the electrostatic charge give you any new meaningful information?

The article's link in PubMed.

H1N1 Influenza strains contain H5N1 genetic material...Are the young and healthy at risk of a massive cytokine storm induced by virus infection?

Human infection with highly pathogenic avian influenza A viruses (HPAIV) such as H5N1 subtypes are characterized by inner bleedings and a massive overproduction of cytokines known as cytokine storm (Schmolke et al., 2009). Recent reports have linked the genomes of the last three pandemic influenza viruses as having emerged from gene reassortment events and possessing HA genes of avian influenza origin. Thus, these findings provoke the following question: If existing influenza strains (i.e. 2009 H1N1 influenza) undergo gene reassortment similar to H5N1 strains, is it possible that the resulting human adapted form could manifest itself as a deadly pandemic targeting healthy individuals by the onset of a massive cytokine storm?

Review of what the “cytokine storm” is: when the body’s normal immune system overacts to an intruder such as a virus, by overproduction of signaling chemicals (known as cytokines and chemokines) that help mobilize immune cells capable of removing infectious agents from the body. The extremely high levels of cytokines that are produced as a consequence of a healthy immune system are over-exaggerated and fatally damaging to tissues and organs. Death will usually result from multisystem organ failure.

I came across two articles I’d like to reference in regard to this blog. Below is a brief summary of each paper, highlighting the author’s findings which are relevant to this blog topic.

The first paper published in July 2009 in Science (Rebecca J.Garten et al., 2009) involved a large collaborative effort of many authors representing the WHO, CDC, NIH and various health organizations. The objective of this study was to characterize the antigenic and genetic variations of 2009 H1N1 circulating in humans. In their attempts to do this, they analyzed genome sequences isolated from 2009 H1N1 patients with previous strains of influenza including classical swine, human seasonal, American avian, North American and Eurasian swine strains. This paper examines the antigenic capabilities of influenza and how it has evolved overtime resulting in the emergence of pandemic flu strains. The paper provides the lineages and reassortment events that have taken place overtime and which gave rise to three pandemic influenza viruses (1918 H1N1, 1957 H2N2, and 1968 H3N2). The lineage suggests that all three strains originated from nonhuman reservoirs and the HA genes of all, originated from avian influenza virus. Now the most recent 2009 A/H1N1 strain contains a never before seen combination of gene segments which appear to be derived from Eurasian swine and classical swine lineages (Garten et al., 2009).

The second paper, by Schmolke M. et al., 2009 in the Journal of immunology by a group in Germany presents in accordance with numerous reports, the observation that the high fatality rate of avian influenza is a consequence of lethal cytokine storm induced by A/H5N1 virus both in humans and animals (Deng RM. et al., 2008; Claas EC. et al., 1998). The significance of the study is based on the concern of highly pathogenic avian influenza viruses (HPAIV) being directly transmitted to humans as a possible source of a new influenza pandemic. They performed mRNA profiling on human umbilical vein endothelial cells (HUVEC) infected with H5N1 based on the idea that endothelial cells are a major source of cytokines and chemokines, and relevant for systemic viral dissemination. Their results confirm clustering and upregulation of inflammatory/immune response which are accompanied by a massive systemic production of cytokines and chemokines, characteristic of a cytokine storm.

It’s frightening to acknowledge the ongoing threats of the 2009 H1N1 swine flu and the still present Asian avian flu virus (AAV H5N1) and its pandemic potential. In regards to the influenza strain reassortment and antigenic evolution, sequence variation in the gene segments of the H5N1 strain have been shown to contribute to viral virulence. It will be interesting to compare the updated sequencing of gene segment among the 2009 H1N1 strains with previously pandemic strains which could suggest whether it may or may not be likely to elicit such a strong cytokine response associated with highly virulent strains such as H5N1.

Based on the recent publications mentioned above I think it is obvious that 1) the new swine flu influenza A strain appears to be a combination of previous bird, swine and human genetic make-up. In addition, all three show lineage to have originated from avian flu. 2) H5N1 the highly virulent avian flu strain causes lethal cytokine storm in young and healthy individuals. These ideas together implicate that H1N1 viruses have pandemic potential and historically support the possibility that healthy young adults may be more susceptible to severe infection due to a strong immune system capable of eliciting a lethal cytokine storm. If uncontrolled, such a cytokine storm occurring in vital organs can lead to organ failure and death.

What would be the best approach in preventing an influenza pandemic or in addressing the potential damage it could elicit by inducing a cytokine storm in infected individuals? Should health officials stringently monitor strains of the 2009 A(H1N1) virus for any antigenic and genetic changes? In the case of infected patients, should the use of prophylactics such as immune suppressors or antivirals be used to minimize the possibility of the cytokine storm?

References:

Garten RJ et al., 2009. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science. 325:197-201.

Schmolke M, Viemann D, Roth J, Ludwig S. 2009. Essential impact of NF-κB signaling on the H5N1 influenza A virus-induced transcriptome. J Immunol. 183:5180-5189.

Deng RM, Korteweg LC, Gao Z, McNutt MA, Ye J, Zhang I, Gu J. 2008. Distinctly different expression of cytokines and chemokines in the lungs of two H5N1 avian influenza patients. J Pathol. 216:328-336.

Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF. 1998. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet. 351:472-477.

Genetic Variation In The Maintenance of HIV Seronegative Status Among High-Risk Populations

Chemokine receptors have proved to be important in maintaining seronegative status among individuals who have a high risk for contracting the HIV virus. Cultures of lymphocytes and macrophages have shown that those who are relatively resistant to HIV infection secrete high levels of co-receptors CCL3, CCL4, and CCL5 when they are inoculated with this virus. It has been discovered that HIV resistant people are homozygous for an allelic, nonfunctional version of the CCR5 co-receptor, D32. In the Caucasian population, the prevalence of this frameshift mutation (coupled with a protein truncation) in the homozygous form is fairly high at about 1%. The heterozygous allelic form of this mutation may provide some modest protection against the sexual transmission of the HIV virus, and could even slow the progression of existing infections. In addition to this, variation in the promoter region of the CCR5 gene has been identified in both Caucasians and African Americans. Differences in promoter regions have also been associated with different rates of progression of the disease. This evidence shows that CCR5 is the major macrophage and T-lymphocyte co-receptor used by HIV to establish initial infection. Interestingly, this also offers hope that primary HIV infection can be blocked by anti-CCR5 receptors.

Janeway, Charles. Janeway's Immunology - 7th Edition / Kenneth Murphy, Paul Travers, Mark Walport. Garland Science. 2008.

Worm therapy available--legally?

Scraping my net over the bottom of the Web, I found Ovamed GmbH, a company in a village near Hamburg that claims to be licensed by the Thai Ministry of Health to sell TSO (Trichuris suis ova) for treatment of Crohn's and UC in those "with a medical recommendation."

And another outfit, Autoimmune Therapies, will sell you a similar product. Here's what they say: "Helminthic therapy, nature's most powerful probiotic, harnesses nature to heal, restoring the helper organisms we co-evolved with and that our immune systems depend on to function correctly, and is based on sound science. Stop treating the symptoms, fix the problem." You can judge for yourselves the accuracy of those statements. They say they sell anywhere except the USA.

There are many more, springing up all over the world, wherever evidence-based medicine is not currently the fashion.