Finding the holy grail of idiopathic pulmonary fibrosis research
Reversing the scarring that occurs in the lungs would revolutionise treatment for this condition.
Having pulmonary fibrosis feels like your lungs are turning to stone over time. As the scarring spreads all the way through the lung, you find it harder and harder to breathe. It feels like the walls are closing in. What’s worse is that this is happening to you, without any chance of healing the already scarred parts of your lung. It’s only going to get worse and eventually you’ll succumb to the disease.
Idiopathic pulmonary fibrosis (IPF), the most common type of fibrosing lung disease, claims the lives of around 6,000 people a year in the UK — more people than are killed by leukaemia. You can get treatment for it now, but all that it will do is slow down the scarring that tries to shut down every last breath.
For many years, scientists have tried to understand what causes some people to develop fibrosing lung disease and what factors influence the spread of the disease within the lung. To understand how IPF works, we need to understand what fibrosis is and what it does.
Under normal circumstances, fibrosis occurs as part of the body’s response to injury. For example, if you accidentally cut your finger with a knife, your body will switch on signalling pathways in your finger which will close up the wound. The signals activate the production of cells called fibroblasts. Fibroblasts are versatile wound healers; they manufacture the collagen and other structural proteins which repair the damaged tissue. They can also transform into myofibroblasts, which are used to build new muscle tissue. Once the wound is fully healed, the signalling pathways are switched off.
If these signalling pathways are broken in such a way that they are turned on constantly, or where they are directed to the wrong place, that leads to excess scar tissue production. Scientists wanting to tackle IPF have two options — either stop the gene(s) and/or molecule(s) which are causing the fibrosis mechanism to start up at the wrong times or in the wrong places, or block or attenuate the parts of the signalling pathway to stop the fibrosis from spreading.
Unravelling these signalling pathways is a long and complex task, but scientists may now be approaching a breakthrough in targeting those parts of the network which drive fibrosing within the lung. They’ve looked at a class of proteins called cytokines — tiny proteins which act as little messages between cells. Cytokines are involved in immune system signalling, so the production of cytokines tells the immune system that neighbouring cells are damaged or are under attack.
Most importantly, cytokines are known to be involved in recruiting and producing fibroblasts, so on one level they are linked to the scar tissue forming process that occurs in people with IPF.
Interleukin-11 is just one of many hundreds of cytokines, but it came to the attention of researchers who study IPF because of where it was being produced. More interleukin-11 was produced in the lungs of patients with IPF, compared with healthy patients. The inceased production was detected specifically in lung fibroblasts too, which meant that it must be involved in wound healing within the lung.
A team of top scientists from the UK, USA, Germany and Singapore wanted to expand on these promising results. They wanted to be sure that the increased production of interleukin-11 was directly related to increased scarring of the lung and to find out which signalling pathways were being switched on or off as a result of greater production of interleukin-11.
The scientists confirmed that interleukin-11 was produced at high levels in lung fibroblasts and, when fibroblasts grown in the lab were treated with interleukin-11, the cells started turning into myofibroblasts, creating the characteristic scarring seen in the lungs of people with IPF. This result was significant as it meant that interleukin-11 was speeding up, rather than slowing down, the creation of new scar tissue.
They wanted to take this result one step further. Knowing that interleukin-11 accelerates scarring, they wanted to see if blocking its production would stop the scarring altogether. Using a mouse model where you can test treatments on lung fibrosis, the researcher administered antibodies which bind to interleukin-11 and stop it from working. They started the process of fibrosis by injecting the mice with an antibiotic called bleomycin and then treated the mice with either an antibody which blocked interleukin-11 or an antibody which did not specifically block interleukin-11. The treatment was given at different points, to see how the blocking antibody affected the build-up of scar tissue during different stages of the disease.
Scar tissue production was assessed by measuring the amounts of the proteins which form the basis of scar tissue (collagen and other structural proteins) and measuring the expression of the genes which make these scar tissue proteins.
This was a well-thought out strategy, but there was a chance that things wouldn’t work as they expected. Many signalling pathways have multiple proteins which perform the same function, meaning that they have a backup plan if things go wrong. It’s also possible that blocking a gene or protein could have unexpected negative impacts on other essential processes (known as a pleiotropic gene). If interleukin-11 was pleiotropic, its potential as a target for treatment would be limited because of the risk of major side-effects when it is blocked.
The results surpassed their expectations. As expected, the mice treated with the interleukin-11 neutralising antibody have much less scar tissue produced during the early stages of the disease. But, when the mice were treated with blocking antibody after most of the scar tissue had already formed, the amount of scar tissue produced in the lungs was also reduced.
Professor Toby Maher, British Lung Foundation Chair in Respiratory Research at Imperial College London, explains the clinical significance of this result:
“The big prize in IPF research has been to find something which can reverse the scarring which causes so many lives to be shortened by IPF. Prognosis for this disease is dreadful, with an average life expectancy of 3 years after diagnosis. The need for treatments which can turn the tide is urgent.
“It’s not been easy to find the molecules which cause the excess scar tissue formation we see in IPF. It’s really exciting that, for the first time, we’ve demonstrated that fibrosis isn’t irreversible and that there is a viable way to stop the damage that abnormal scar tissue does to the lungs of people with IPF.
“Finding drugs which target interleukin-11 is now a top priority, as it offers the best chance yet of a life-saving treatment for IPF.”
The full paper is available in Science Translational Medicine.
