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The lungs – a still largely unknown organ

Paul Dietl talks around the subject before coming to the point: yes, lung research has a very long tradition. And yes, the breathing mechanism and structure of the lungs have been known for many years. We have also known for quite some time that gases diffuse and are not actively absorbed in the lungs. Are lung researchers now concentrating on the precise details? Nothing could be further from the truth, said the Ulm professor for general physiology, Prof. Paul Dietl: “The most essential aspects are still unclear.”

Prof. Paul Dietl, expert in cellular lung physiology © Paul Dietl

The quantity of research that needs to be done equals the quantity of details known. It is wrong to believe that an understanding of the most important causes of diseases is the inevitable result of sufficient research. Dietl points out that the causes of emphysemas, of what is known as "lung remodelling" and of all chronic lung alterations caused by smoking or harmful substances are still unknown. This is also the case for pulmonary hypertension and some types of lung fibroses.

A basic research-oriented lung researcher such as Dietl is nevertheless a fairly rare beast both in the discipline of general physiology and in his faculty as a whole. Despite the considerable gaps in knowledge, university lung research is underrepresented in German-speaking countries, in contrast to Anglo-American countries. Back when tuberculosis was a matter of public concern in the 19th and 20th centuries, the area of pulmonology was generally dealt with in nursing homes. In Germany, tuberculosis research is generally carried out in the laboratories of pharmaceutical companies.

The lungs are much more important in the clinical field, particularly when it comes to lung diseases and also because of the role the lungs play in cardiac diseases and systemic diseases such as autoimmune diseases. Two clinical research institutions were recently established in Germany, but Dietl still considers that basic research-oriented lung research continues to be underrepresented.

Difficulties and methodological limitations

Moreover, there are a number of methodological limitations associated with lung research. It is still very difficult to enter the ultra fine branches of the lungs, which means that researchers cannot gain detailed insights into the tiny lung branches. Dietl also considers that the development of cellular models, artificial lungs and animal models is quite difficult. All things considered, he believes that the currently available methods are unsuitable for investigating intact lung tissue. He also believes that in many cases, mice are unsuitable models; he believes that pigs could be suitable models, albeit relatively expensive.

If the lung changes its structure, for example due to long-term smoking, this automatically affects the gas exchange. Disorders in the ramifications of the bronchia can only be discerned indirectly, and although they can be diagnosed, it still takes a long time before the disease symptoms become obvious during which time a lot can happen. According to Dietl, the difficulty in accessing the terminal structures of the lungs is one of the major problems in lung research.

“The deeper one delves into the lung, the more obscure it becomes.” The lung researcher from Ulm and his 15-member team hope that their research will shed some light on the basic regulatory mechanisms that still require clarification. “It is important to be aware of what one does not know,” said Dietl highlighting the priority of their research.

Research at the border between air and liquid

A complex biophysical area: the border between air and liquid. An alveole releasing surfactant is shown at the bottom of the picture. © Paul Dietl

Complex protection mechanisms of the lung, whose 500 million alveoles form a huge area of about 140 square meters, keep the alveoles open and ensure that the air flows continually and gases are exchanged. According to Dietl, these interactions between air and liquid are a very complex biophysical area whose underlying mechanisms are still not understood in detail.

For example, it is still not known how the air that we breathe in reaches all 500 million alveoles. It is also not known how the thickness of the mucous membranes that form the inner lining of the lungs to absorb pollutants is regulated. This mucous membrane, which is covered by cilia that sway back and forth, clears harmful substances and dust particles out of the lungs. This protective mucous layer requires a layer of fluid to float on. But it is still not known where this fluid comes from and how its thickness is regulated. So far, all the ideas relating to the origin of this fluid are only assumptions.

What is the effect of mechanical forces?

Schematic representation of an alveole whose cell makes the lungs smooth by excreting a surfactant. © Paul Dietl

Professor Dietl’s research focuses on the border between air and fluid. The term “mechanotransduction” probably best describes his research.

Important physiological processes happen at the border between air and fluid. Dietl’s team mainly focuses on the excocytosis of surfactants. Type II lung cells produce and secrete this vital substance into the lumen of the alveoles. The mixture of phospholipids and proteins, which is only found in the lungs, is a physical barrier that protects the lungs against intruders. It also makes the alveoles smooth and flexible. Acute lung failure (adult respiratory distress syndrome) results from the reduced or disordered function of this surface-active substance, for example during artificial respiration which causes the cells to overstretch.

Paul Dietl’s team is also trying to find an answer to a question that uncovers basic physiological principles not only relating to the lungs: how can a mechanical stimulus generate a (bio)chemical reaction and vice versa? Dietl is focusing on type II pneumocytes where he is hoping to find out what happens when the cells, which expand during breathing, trigger the release of the surfactant. Dietl believes that this substance must have a special composition that changes its properties in relation to the radius of the alveoles.

From attachment to release

It is still not known what triggers the process of exocytosis. However, lung researchers do agree on the phases of this complex process. © Paul Dietl

The Ulm researcher uses fluorescent dyes to see how the cells change shape when they expand. Under the microscope, Dietl managed to observe how the cells excrete this complex substance. Many details relating to the process of exocytosis are now known. However, it is still largely unknown how the mechanical signal of expansion is transferred to the cell and how the biochemical process cascade leading to the excretion of the surfactant is initiated. The surfactant is stored in large vesicles known as lamellar bodies. These stores need to fuse with the plasma membrane in order to release their contents into the alveolar space. The fusion happens in several steps: a fusion pore is formed through which the protein-fat mixture is excreted. The pore itself limits the extent of surfactant released.

Which impulse comes first?

What triggers exocytosis? Dietl has two possible explanations: either the expansion of the cell caused by breathing or the G-protein coupled P2Y receptor activated by extracellular ATP. The first explanation seems to be more plausible, and, the second, although it is less probable, cannot be completely excluded. The two hypotheses have one thing in common: the calcium ion concentration needs to increase in the cytoplasm. However, the molecular mechanisms that trigger this increase are still unknown. Researchers around the world are debating whether this mechanism is triggered by channels through which the calcium ions enter the type II pneumocytes. Despite many competing models designed to explain this phenomenon it does not appear possible that exocytosis is triggered by a single mechanism or by a single bioactive molecule.

Actin accelerates the process

According to the current state of knowledge, the process of exocytosis is divided into three steps that are controlled in different ways. Each of these steps might affect the release of the surface-active substance. Recent experiments carried out by Dietl and his team suggest that motor proteins such as actin are required. They assume that actin surrounds the lamellar bodies like a coat, thereby squeezing the substance out of the cell.

Dietl does not envisage quick success since these basic mechanisms have a role that is far too elementary. However, he does believe that answers to these questions lead to a better understanding of the lungs and provide lung researchers with tools that enable the treatment of more than just the symptoms of common lung diseases.

Overview of state-of-the-art research:
Paul Dietl, Birgit Liss et. al. : Lamellar Body Exocytosis by Cell Stretch or Purinergic Stimulation : Possible Physiological Roles, Messengers and Mechanisms, in: Cellular Physiology and Biochemistry 2010; 25; pp. 1-12.

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