Preclinical efficacy testing

Asthma is defined as a chronic inflammatory disease of the airways. It affects 4 to 5 percent of the population worldwide. Symptoms of asthma are attacks of breathlessness and wheezing, airflow obstruction, and bronchial spasm. On the cellular level, asthma is characterized by allergic inflammation and structural changes in the airways including goblet cell hyperplasia and smooth muscle thickening. The allergic inflammation is dominated by immune cells such as eosinophils and allergen-specific TH2 lymphocytes. High amounts of inflammatory mediators such as TNF-α, interleukin (IL)-1, IL-4, IL-5, and IL-13 are produced and elevated in bronchoalveolar lavage of patients. These cytokines are known to support the inflammation and the allergen-specific TH2 response. Additionally, chemokines such as eotaxin, IL-8, RANTES, and MCP-1 are released to support the migration of further immune cells which keep the allergic inflammation and its symptoms going.

At Fraunhofer ITEM, we have different models to induce features of asthma, including ex-vivo human tissue models and in-vivo murine and non-human primate models.

Acute and chronic allergic airway inflammation:

• Ovalbumin-induced acute allergic asthma in mouse or rat
• House dust mite (HDM)-induced severe asthma in mouse
• House dust mite (HDM)-induced subacute asthma in marmoset

Fresh human lung tissue:

• Asthma in fresh human lung tissue

The common chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity and mortality. More than 200 million people worldwide are affected by COPD, making it the fourth leading cause of death. COPD is characterized by progressive destruction of the lung parenchyma, resulting in the development of emphysema, increased mucus production, and chronic airway inflammation. It is a highly heterogeneous disease. Cigarette smoke has been shown to be the most important risk factor for the development of COPD; but also burning of biomass fuels and occupational exposure are known to be COPD risk factors.

At Fraunhofer ITEM, we use primary cells, cell lines, fresh lung tissue, and animal models to induce features of COPD. Lipopolysaccharides (LPS), cigarette smoke, and cigarette smoke condensate are applied as agents. LPS-induced inflammation mimics primarily an acute and subacute inflammatory process in the lung. We have models of LPS-induced inflammation in laboratory animals including non-human primates, in fresh lung tissue and cells. Cells and tissue can also be exposed to cigarette smoke condensate and cigarette smoke. This is done primarily at the air-liquid interface. In particular the exposure of cells and tissue at the air-liquid interface is considered to closely reflect the human situation.

Acute and subacute respiratory inflammation:

• LPS-induced respiratory inflammation

Fresh human lung tissue and cells:

• COPD in fresh human lung tissue

Inflammation is an essential component of many respiratory diseases, including pneumonia, asthma and chronic obstructive lung disease (COPD). It can be classified as acute or chronic. Acute inflammation is a natural, self-protecting biological response of the body to harmful agents such as physical or chemical injury and pathogens. It is characterized by release of proinflammatory mediators, migration of leukocytes, and initiation of repair processes. These events help prevent bodily injury, eliminate the initial cause of injury, and clear out cell debris. In chronic inflammation, a prolonged inflammatory condition with a progressive shift towards tissue destruction, scarring and remodeling is observed. It is known that chronic inflammation underlies not only respiratory infectious diseases, but also cancer and autoimmune disorders such as asthma and COPD. This realization makes it possible to recognize chronic inflammation as a condition that should be treated by its own and opens new avenues for treatment.

At Fraunhofer ITEM, we have a broad range of different models to induce acute and chronic inflammation, from in-vitro models using primary cells and cell lines to ex-vivo human tissue models and in-vivo murine and non-human primate models. Please click below for a description of our acute and subacute respiratory inflammation models. Our chronic inflammation models are described under Asthma, COPD, and Infection.

Acute and subacute respiratory inflammation:

• LPS-induced respiratory inflammation

Fresh human lung tissue and cells:

• Innate immune response in human lung tissue

Pulmonary disorders are among the most common medical conditions worldwide. Pulmonary fibrosis represents a severe and fast progressing lung disease, causing irreversible dysfunction of the organ. The disease is characterized by aberrant wound healing, excessive proliferation of fibroblasts, uncontrolled deposition of extracellular matrix, and destruction of the cellular architecture of the lung. So far, only two pharmacological treatments have been approved as anti-fibrotic drugs for clinical application (pirfenidone and nintedanib). However, both treatments can only slow down the progression of the disease and appear to cause serious side effects. In most cases, organ transplantation is the only option for patients. Hence, understanding the molecular mechanisms that are involved in the onset and progression of fibrotic response is an unmet medical need for the development of novel and more efficient treatments.

At Fraunhofer ITEM, a range of models to induce pulmonary fibrosis are established. This includes routinely employed and well-characterized in-vitro and in-vivo models to assess the pharmacological efficacy of new treatment options. In addition, a physiologically relevant ex-vivo model can be provided which enables investigation of important signaling pathways at different stages of the disease. The ability to conduct toxicological studies and clinical phase-I trials further complement the portfolio for translational fibrosis research at Fraunhofer ITEM.

Fibrosis:

• Bleomycin-induced pulmonary fibrosis in animals (IPF model)
• Fibrosis in fresh human lung tissue

Infectious diseases of the respiratory tract are among the major health problems worldwide, having a high economic impact every year. They can be caused by viruses and bacteria. The pathogens affect either the upper or lower respiratory tract or both, resulting in a broad spectrum of medical conditions. Ninety percent of infections of the upper respiratory tract are of viral origin. Bacterial infections of the upper respiratory tract are less common than viral infections. Differentiation is difficult, due to the similarity of the symptoms of viral and bacterial infections.

Influenza virus, parainfluenza virus, rhinovirus (HRV), and respiratory syncytial virus (RSV) are viruses that are associated with common cold. Among these, rhinovirus is the infectious cause of more than 80 percent of colds. In immunocompetent adults, the infection is often asymptomatic or associated with a simple common cold. In immunocompromised patients or people suffering from chronic respiratory disorders such as asthma or COPD, however, viral infection can induce serious worsening of symptoms. RSV is the major cause of severe respiratory infection in infants.

Bacterial pneumonia is an infection of the lungs which, if untreated, can progress towards serious conditions leading to respiratory failure or death. In particular people with underlying chronic diseases are at a higher risk of developing severe pneumonia. In this context, Pseudomonas aeruginosa is the most common pathogen isolated from patients.

At Fraunhofer ITEM, we have different models to induce pneumonia: in vitro in cells or cell lines, ex vivo in lung tissue, and in vivo in murine models.

Infection:

• Pneumonia caused by bacteria
• Pneumonia caused by viruses