Pathogenesis of community-acquired pneumonia, chronic obstructive pulmonary disease and cystic fibrosis: mechanism of inflammatory response and the role of Th17 differentiation

Community acquired pneumonia remains a common and serious illness despite
antimicrobial therapy. Major gaps remain in the understanding of the
pathogenesis of this deadly infection. Why can some individuals easily control
small bacterial challenges and remain healthy, whereas others develop strong
and potentially fatal respiratory infections? A number of factors are known to
influence a patient's susceptibility to specific pathogens in CAP, including
age, disease severity at presentation, immune status and local susceptibility
patterns. Studies in mice show that survival is associated with a strong
inflammatory response early in the course of infection and rapid bacterial
clearance. Whereas death is associated with a failure of the host*s immune
system to control the growth of bacteria, leading to a even more powerful
inflammatory response later in the course of infection, with tissue injury,
shock and death as a result. Remarkably, a unique subset of effector T cells
was recently described, termed Th17, which produces the pro-inflammatory
cytokine IL-17. These cells control a wide range of infections at mucosal
surfaces and have been implicated in the pathogenesis of several autoimmune
diseases first thought to be caused by deregulated Th1 cell function. Emerging
data have also suggested that Th17 plays an essential role in the host defense
against extracellulair bacteria by induction of neutrophil-mediated protective
immune response and through regulation of cell-mediated immunity.
Interestingly, increased IL-17 concentrations have also been implicated in the
pathology of autoimmune disorders, such as systemic lupus erythematosus (SLE)
and rheumatoid arthritis (RA), but also to disease pathology in allergic
asthma, chronic bronchitis, cystic fibrosis, acute respiratory distress
syndrome and COPD (chronic obstructive pulmonary disease). COPD is
characterized by progressive development of airflow limitation and attributed
to long-term exposure cigarette smoke. The cytokines IL-6 and IL-17 are also
central to mucus production by airway epithelial goblet cells. Exacerbations of
COPD are associated with increased numbers of neutrophils in the airways,
likely recruited by IL-1b and IL-17-dependent mechanisms. COPD shares
similarities with autoimmune diseases as Rheumatoid arthritis (RA), with a
possible central role of Th17 cells, to newly created or altered epitopes,
induced by tobacco smoke.
The pathophysiology of Cystic Fibrosis (CF) is characterized by chronic airway
infection and inflammation that starts early in life. This leads to progressive
worsening of the lung function, resulting in damage to the airways and,
ultimately, death.The mechanisms that lead to the development of sustained and
predominantly neutrophilic inflammatory response, and the ultimate destruction
of the lung over decades remains unclear. Recently, a study has shown that
concentrations of IL-17 were markedly elevated in sputum of 8 patients
undergoing pulmonary exacerbation.
In this study, we aim to identify the role of mechanisms of action of
Th17-lineage cells in COPD, pneumonia and CF pathogenesis. Therefore, the local
inflammatory response in COPD, CF and pneumonia will be studied in humans in
different materials, like blood specimens, bronchoalveolar lavage, sputum and
lungtissue obtained from lungtransplantation. By performing such a study we can
compare the results with studies already performed in mice. When a strong
inflammatory response in pneumonia leads to a bad prognosis, then this could be
an indication for starting anti-inflammatory therapy, including
corticosteroids, besides antimicrobial treatment. If IL-17 is considered an
important pathogenic factor of T-cell mediated inflammation in pneumonia, then
IL-17 could be a promising therapeutic target of the disease. As IL-17 is
proven to be a key factor in chronic inflammation, which is thought to play a
crucial role in deteriorating lung function in COPD and CF, then IL-17 may
serve as a target for ameliorating the effects of neutrophil-mediated chronic
airway inflammation.

To assess whether Th17 cells play a central role in COPD, CF and pneumonia
pathogenesis

The study will be conducted as a prospective cohort study in an observational
design.

Peripheral blood collection
This is a routine procedure, which is performed in many patients. Possible side
effects are a vaso-vagal collaps or hematoma.

Bronchoscopy
Pulmonary physicians frequently use bronchoscopy to obtain material from the
airways for microbiological or pathological reasons. In general it is a safe
procedure. Performing a BAL can cause temporarily complaints of coughing, after
some hours a temporarily period of fever can appear. In case of fever
antibiotics are not indicated, since the fever will disappear after 24 hours.
Sometimes patients can become hypoxemic, which will be monitored by the
pulse-oximeter. In case of hypoxemia the patient will receive O2 until a
maximum of 4 liters and the investigation will be terminated After an
endobronchial mucosal biopsy some blood loss can occur, which often
spontaneously resolves very quickly.
A pubmed search identified 384 articles, in which BAL was performed in healthy
controls. Data from literature showed that BAL was a safe procedure in this
group.

There is no direct benefit for the individual patient on the short term.