Potential Cause of Asthma Discovered May Also Lead to Cure

Cardiff scientists have for the first time identified the potential root cause of asthma and an existing drug that offers a new treatment.


Published today in Science Translational Medicine journal, University researchers, working in collaboration with scientists at King's College London and the Mayo Clinic (USA), describe the previously unproven role of the calcium sensing receptor (CaSR) in causing asthma, a disease which affects 300 million people worldwide.

The team used mouse models of asthma and human airway tissue from asthmatic and non-asthmatic people to reach their findings.

Crucially, the paper highlights the effectiveness of a class of drugs known as calcilytics in manipulating CaSR to reverse all symptoms associated with the condition. These symptoms include airway narrowing, airway twitchiness and inflammation - all of which contribute to increased breathing difficulty.

"Our findings are incredibly exciting," said the principal investigator, Professor Daniela Riccardi, from the School of Biosciences. "For the first time we have found a link airways inflammation, which can be caused by environmental triggers - such as allergens, cigarette smoke and car fumes – and airways twitchiness in allergic asthma.

"Our paper shows how these triggers release chemicals that activate CaSR in airway tissue and drive asthma symptoms like airway twitchiness, inflammation, and narrowing. Using calcilytics, nebulized directly into the lungs, we show that it is possible to deactivate CaSR and prevent all of these symptoms."

Dr Samantha Walker, Director of Research and Policy at Asthma UK, who helped fund the research, said:

"This hugely exciting discovery enables us, for the first time, to tackle the underlying causes of asthma symptoms. Five per cent of people with asthma don't respond to current treatments so research breakthroughs could be life changing for hundreds of thousands of people.

"If this research proves successful we may be just a few years away from a new treatment for asthma, and we urgently need further investment to take it further through clinical trials. Asthma research is chronically underfunded; there have only been a handful of new treatments developed in the last 50 years so the importance of investment in research like this is absolutely essential."

While asthma is well controlled in some people, around one-in-twelve patients respond poorly to current treatments. This significant minority accounts for around 90% of healthcare costs associated with the condition.

According to Cardiff Professor Paul Kemp, who co-authored the study, the identification of CaSR in airway tissue means that the potential for treatment of other inflammatory lung diseases beyond asthma is immense. These include chronic obstructive pulmonary disease (COPD) and chronic bronchitis, for which currently there exists no cure. It is predicted that by 2020 these diseases will be the third biggest killers worldwide.Professor Riccardi and her collaborators are now seeking funding to determine the efficacy of calcilytic drugs in treating asthmas that are especially difficult to treat, particularly steroid-resistant and influenza-exacerbated asthma, and to test these drugs in patients with asthma.

Calcilytics were first developed for the treatment of osteoporosis around 15 years ago with the aim of strengthening deteriorating bone by targeting CaSR to induce the release of an anabolic hormone. Although clinically safe and well tolerated in people, calcilytics proved unsuccessful in treating osteoporosis.

But this latest breakthrough has provided researchers with the unique opportunity to re-purpose these drugs, potentially accelerating the time it takes for them to be approved for use asthma patients. Once funding has been secured, the group aim to be trialling the drugs on humans within two years.

"If we can prove that calcilytics are safe when administered directly to the lung in people, then in five years we could be in a position to treat patients and potentially stop asthma from happening in the first place," added Professor Riccardi.

The study was part-funded by Asthma UK, the Cardiff Partnership Fund and a BBSRC 'Sparking Impact' award.

Cold Related Airway Damage | Exercise-Induced Asthma

Scientific studies indicate that up to 50% of people chronically exposed (athletes, recreationalists, workers, etc.) to cold weather experience some respiratory symptoms, including a decline in lung function compatible with exercise-induced asthma. Most of these people have neither a prior history of asthma nor a family history of asthma. (Storms W. Review of Exercise-Induced Asthma, Medicine and Science in Sports and Exercise , 2003; 35:1464-1470).

According to the Asthma & Allergy Foundation of America , asthma and allergies strike 1 out of every 4 Americans. Asthma symptoms can be caused by dry cold air inhaled into the lungs, resulting in inflamed, clogged and constricted airways. Symptoms include difficulty breathing, wheezing, coughing tightness in the chest. In severe cases, asthma can be deadly.

Risk Prevention:

According to the American College of Sports Medicine , a counter measure for decreasing the occurrence of cold related airway damage, exercise induced asthma and decreased performance is to protect facial skin while increasing the warmth and humidity of inhaled air without decreasing airway resistance when breathing rates are high.

The ColdAvenger was designed by physician, in following the counter measures recommended by the American College of Sports Medicine , to combat the above damaging effects of cold air. The ColdAvenger achieves the following 6 specific design elements:

1. Thermal protection from the elements

2. Free breathing, both in and out

3. Humidifies inhaled air

4. Warms inhaled air

5. Keeps face dry through moisture management

6. Prevents goggles from fogging

The size and shape of the ventilator chamber of the ColdAvenger is the key to achieving these goals. The specific volume of air created by the ventilator dynamically mixes inhaled cold air with exhaled warm air to achieve a perfect balance of warmth and humidity. The ventilator design allows for ease of breathing while at rest or during extreme exertion. Moisture in exhaled air bonds to the polyurethane keeping it away from the face, any excess moisture buildup escapes via the designed drain ports and is kept off facial skin. Moisture management is important to prevent ice formation on the sensitive skin around the nose and lips.

Real-Time Tests:

1. Ventilation: A real-time probe measured percent O2 and CO2 inside and outside the ventilator. Percent O2 and CO2 during inhalation and exhalation were very similar to normal control without the mask, indicating more than adequate movement of air through the ventilator and no accumulation of CO2. The O2 measured during simulated exercise varied from 21-28% and the CO2 varied from 0.03-3.23%, which are both normal values.

2. Humidity: Humidity inside the chamber varied from 70-80% with an internal temperature of 66°F compared to outside humidity of 15% and temperature of 5°F.

3. Resistance: Ease of breathing was tested using a Dwyer Series 77 Digital Manometer to measure in-mask pressure during simulated light, medium, and heavy breathing. Fluctuations in pressure were ±5 inches of water, indicating minimal resistance during the heaviest of breathing.

4. Temperature: Digital thermometry during skiing, jogging, walking and standing demonstrated an in-mask air temperature range from 40°F to 60°F higher than outside air.

Check out more on the ColdAvenger line of cold weather face masks http://coldavenger.com.

"I have asthma…"

I have asthma and have been watching out the window when my wife or daughter snow blows the driveway because of the cold air. When it usually got below 25 degrees I would make it a point to stay in the house and in Chicago, that was most of the winter. I have been out in below zero temperature wearing the mask to the car and then removing it once I’m in the car and then putting it back on before I get out of the car to walk into the house or store. This mask has given me my life back in the winter. The only down side is now “I” go out with the mask on and snow blow the driveway even when it’s cold and my wife watches out the window from inside the house.

All joking aside, it makes a guy feel pretty bad watching out the window as his wife snow blows the driveway and now I can smile and tell her stay in the warm house and I will take care of the driveway.

Thanks,

Dave, Chicago

____

"Military Operations"

“First airborne jump in the arctic circle, sustained zero cold weather injuries. The ColdAvenger mask is ideal for these freezing temperatures to mitigate cold weather injuries due to taking off layers or fogging over goggles.”

William C Stanley, SGT USARMY

Researchers one step closer to developing asthma vaccine

Researchers at VIB (a leading life sciences institute in Flanders, Belgium) and Ghent University have successfully established a causal relationship between exposure to so-called farm dust and protection against asthma and allergies. This breakthrough discovery is a major step forward towards the development of an asthma vaccine. The results of the research were published in the leading journal Science.

It is commonly known that drinking raw cow's milk can provide protection against allergies. A 14-member research team, led by professors Bart Lambrecht and Hamida Hammad (both associated with VIB and Ghent University) has now established a solid scientific basis for this claim.

Many years ago, it was found that children growing up on farms are far better protected against asthma and allergies. However, until recently, scientists were unable to pinpoint why this is the case.

Prof. Bart Lambrecht (VIB/Ghent University/Ghent University Hospital): "At this point, we have revealed an actual link between farm dust and protection against asthma and allergies. We did this by exposing mice to farm dust extract from Germany and Switzerland. These tests revealed that the mice were fully protected against house dust mite allergy, the most common cause for allergies in humans."

In addition to the causal relationship, the scientists discovered the mechanism behind this: farm dust makes the mucous membrane inside the respiratory tracts react less severely to allergens such as house dust mite.

Prof. Hamida Hammad (VIB/Ghent University): "This effect is created by the A20 protein, which the body produces upon contact with farm dust. When we inactivate the A20 protein in the mucous membrane of the lungs, farm dust is no longer able to reduce an allergic or asthmatic reaction."

These findings were then tested in patients. The results showed that people suffering from allergies and asthma have a deficiency in the protective protein A20. It explains why they react to allergens so severely.

Prof. Bart Lambrecht (VIB/Ghent University/Ghent University Hospital): "We also assessed a test group of 2,000 children growing up on farms, and found that most of them are protected. Those who are not protected and still develop allergies have a genetic variant of the A20 gene which causes the A20 protein to malfunction."

Clear prospects for the future
The team's conclusions have opened up several possibilities for future research. At the moment, they are trying to identify the active substance in farm dust that is responsible for providing protection. Once this has been identified, the development of a preventive medicine against asthma may be the next step.

Prof. Hamida Hammad (VIB/Ghent University): "We already suspect that to some extent, the answer lies in the endotoxines, which form part of the cell wall of specific bacteria. There are very likely other contributing substances as well. Discovering how farm dust provides this type of protection has certainly put us on the right track towards developing an asthma vaccine and new allergy therapies. However, several years of research are required still before they will be available to patients."

Read more at News Medical

New research finds ozone in smog may cause asthma

smogIt's completely invisible, but the distinctive smell of electrical discharge after photocopying is a tell-tale sign of ozone in the air. Ozone is a component of what we refer to as 'smog' and on hot sunny days, in cities with high traffic volumes, more ozone is formed.

It's a problem, particularly for people with pre-existing respiratory diseases, the very young and the elderly. Some epidemiological studies suggest that long-term exposure to ozone could play a role in the development of asthma, but there has been little physiological data available to underpin these observations.

Now, new research conducted by scientists at the Universities of Melbourne and Wollongong and QUT has provided a first glimpse at how free radical damage might be initiated in the human lung upon exposure to the urban air pollutant ozone.

The research team led by Professors Stephen Blanksby, QUT and Richard O'Hair, Bio21 Institute, from the ARC Centre of Excellence for Free Radical Chemistry has used a powerful combination of electrospray ionisation coupled with multistage mass spectrometry experiments to shed light on how radicals are formed in the reactions of ozone with models of lung proteins. Their work is featured in the current edition of Angewandte Chemie International Edition (link is external).

The team studied how the deprotonated form of the amino acid cysteine and related amino acids and peptides react with ozone when isolated under idealized near-vacuum conditions, and tracked the formation of primary oxidation products including radicals.

"Free radicals are 'unhappy' molecules that have an unpaired electron and so tend to react with other molecules around them, initiating a cascade of chemical transformations. When this occurs in the body, such as at the lining of the lung, damage occurs, which ultimately may result in inflammation and breathing difficulties," said Richard O'Hair, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne.

"We have observed that the amino acid cysteine – a component of lung proteins – becomes 'radicalised' in the presence of ozone," Richard O'Hair explains.

The team was able to make these observations using a mass spectrometer, where they exposed the amino acid cysteine to ozone in a gas form. Although this is an artificial, controlled environment, outside a biological system, it hints at what may happen in the body and thus provides a potential molecular basis for the physiological mechanism of how ozone contributes to respiratory difficulties.

On days when ozone levels are high, people with asthma tend to experience a reduction in lung function, increased respiratory symptoms and increased frequency of asthma attacks, increased medication and health services use. (US EPA (link is external)).

About 10% of the Australian population (2 million people) currently have asthma, which is large by international standards (Asthma Foundation (link is external)) and lifetime prevalence is up to 11% in some Chinese cities (link is external).

"We hope this work will inspire scientists to search for ozone induced protein free radical formation and damage at the air-liquid interface of the lung." said Professor O'Hair.

Read more at Medical Xpress

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