Obesity could interfere with acute pulmonary inflammation

Researchers from Brazil and King’s College London investigate the protective role of body weight and female sexual hormones in the development of inflammation.

By Silvia Campolim

Agência FAPESP – A controversial question is under investigation in the laboratories of the Biomedical Sciences Institute at Universidade de São Paulo (ICB-USP) and King’s College London. In experiments conducted in mice, researchers seek to determine whether obesity in women interferes with the development of a serious pulmonary condition known as acute respiratory distress syndrome (ARDS), which causes the death of patients in up to 70% of cases.

Researchers Wothan Tavares de Lima, of ICB-USP, and Yanira Riffo Vasquez, of King’s College, who study the development of ARDS resulting from intestinal ischemic trauma, believe that obesity does have such an effect. The two conducted a FAPESP-funded study on the subject.

“Not all patients who suffer from ischemia will have a response such as acute respiratory distress syndrome, but it is not rare, and 50% to 70% of patients with this problem will die,” said Lima, the coordinator of ICB-USP’s Physiopathology Laboratory of Experimental Inflammation.

Ischemia is a momentary interruption in the blood circulation. Traumatic intestinal ischemia can occur in several situations, such as obstruction of the intestine, surgery for the removal of organs or transplants, and accidents with trauma or hemorrhagic shock.

An example is an individual who has his or her spleen or liver punctured in a traffic accident and has severe internal bleeding. To stop the hemorrhaging in emergency rooms, doctors normally pinch arteries and veins around the wound. These maneuvers can lead to ischemia because the blood no longer flows to a certain region.

When the blood no longer flows, cells begin to lack oxygen and other nutrients. Certain cells die, whereas others continue working, albeit inadequately, and release toxic products that normally act in inflammatory processes.

It is estimated that during ischemia, because the blood does not flow, these substances pool at the site of the intervention. However, when the problem is resolved, the blood begins to circulate again – in a process called reperfusion – and the substances are disseminated throughout the body. “The result of this event is sometimes devastating because all organs begin to receive a proinflammatory stimulus,” said Lima.

In general, the lung is the first organ to manifest changes when these toxic products spread. “The inflammatory mediators reach the region of the pulmonary parenchyma, where the alveoli, bronchi and bronchioles are located and where gases are exchanged, and they produce inflammation, which increases vascular permeability,” explained Lima.

The organ begins to accumulate liquid and a large quantity of neutrophils, a type of inflammatory cell, and develops acute pulmonary inflammation, which can evolve into ARDS. “As there are varied situations that can lead to ischemia and cause the syndrome [ARDS], it is very important to understand this process,” said Lima.

Laboratory research

There is still no specific treatment protocol for ARDS, except for maintaining lung function with pharmacological treatments. Doctors also do not know when and how the syndrome occurs, according to Chilean graduate student Yanira Vasquez, who studied at USP before her career took her to King’s College.

Patient weight is the focus of the study. “We want to know if people who are obese are more likley to be protected or exposed to pulmonary inflammation after ischemia and reperfusion”, affirmed Vasquez.

In the ICB-USP laboratory, the scientists developed the models used in the research: two groups of female mice, obese and normal weight. The groups received different diets: one conventional, and the other hyperlipidic. After 10 weeks, the scientists induced ischemia and intestinal reperfusion in the rodents.

“After the diet, we evaluated the group of obese females and the group at normal weight in relation to parameters of the inflammatory response and the migration of cells inside the lung, in addition to the cells produced in the bone marrow,” said Lima. After ischemia is induced, the blood cells migrate to the lungs, but the bone marrow produces new cells to supply the organism.”

At the laboratory at King’s College London – which is specialized in lung disease and has a long tradition of studying the role of platelets in inflammation – the researchers conducted in vitro experiments using the platelets of mice to observe how these cells help other cells to leave the blood vessels and reach the site of inflammation.

“The platelets act as a lubricant, easing the passage of cells, and release a large quantity of inflammatory mediators. Thus, platelets could have a fundamental role in reperfusion after ischemia. We managed to measure the paths of this migration and to deduce what happens in obese animals subjected to ischemia and reperfusion,” said Vasquez.

The researchers’ hypothesis is that whereas platelets are ‘sequestered’ to function at the inflammatory site and are found in reduced numbers throughout the remainder of the body in normal-weight mice after ischemia, obese mice enter the process of ischemia and reperfusion with fewer platelets in the circulation, and nothing happens to the number of platelets in the body. The obese mice therefore avoid possible development of the syndrome [ARDS] through the inflammatory process.

The result of the study should be published soon, according to the researchers, who are currently examining the data and writing articles. ARDS that results from ischemia and reperfusion events is more severe in men than in women, according to previous studies. For this reason, Lima and colleagues are also investigating the role of sexual hormones in respiratory inflammation.