Lung Inflammation and Repair


Pulmonary inflammation induced by bacterial or viral infection is characterized by severe airway and alveolar injury, resulting in uncontrolled local and systemic inflammation, loss of alveolar barrier function and impairment of gas exchange, and the clinical manifestation of acute lung injury/ARDS. A tightly balanced, compartmentalized and spatially controlled immune response is therefore key to protecting the host from the invading pathogen without injuring the delicate alveolar architecture and jeopardizing the vitally mandatory level of gas exchange function. Inflammatory events, immune responses and acute/chronic parenchymal injury may similarly be provoked by non-microbial (particulate, gaseous) attack on the large lung epithelial surface.

The lung epithelium is one of the major pathogen sensors and orchestrators of the initial immune response of the entire body. It elicits a multitude of cell-autonomous stress responses to cope with the invading pathogen, and induces an inflammatory response by instructing circulating and tissue-resident immune cells to fight invading pathogens. This might result in rapid pathogen clearance and maintenance of parenchymal integrity at best, or in extensive tissue destruction with non-contained, systemic inflammation at worst. In fact, the epithelial surveillance mechanisms and cellular communication networks involved in the timely fine-tuning and balancing of these responses need to be tightly adjusted to the requirements of the infected and injured bronchoalveolar compartment, and there is a substantial gap of knowledge on the mechanisms controlling this delicate balance, and why they fail that often, resulting in life-threatening severe acute lung injury.

A critical step in this scenario is the timely and compartmentalized switch from a pro-inflammatory defense status to resolution of inflammation and tissue repair. Macrophage populations of different ontogeny (yolk sac-derived/lung-resident, bone marrow-derived), and further innate immune cells of the lymphocyte lineage are key players herein. Endowed with high functional plasticity such cells may acquire defined phenotypes driving host-defense, inflammation resolution, and tissue regeneration resulting in restitutio ad integrum during the course of infection. However, this functional plasticity seems to be lost in the aging individual. Some crucial macrophage epigenetic enhancers and transcriptional programs have been related to such phenotypes, but the signals derived from the infected and injured lung parenchyma instructing these programs in macrophages (and in further innate immune cells relevant for tissue repair) are currently not well understood, nor are the defined functions of (re-)programmed macrophages within cellular communication networks of parenchymal stem cell niches in the context of lung repair.
Co-ordinated processes of tissue repair from different stem cell pools after injury induced by pathogens or non-microbial (particulate, gaseous) attack are crucial to restore the delicate lung architecture. This requires, beyond regenerative immune cells, the timely interplay of distinct cellular compartments within the parenchymal stem cell niche, including different subsets of mesenchymal cells, vascular cells and epithelial cells with varying levels of stem/progenitor potential. Although the lung possesses an enormous endogenous potential for tissue regeneration, these processes often fail or end in the non-resolving, so-called late-ARDS state with ´aberrant` repair, characterized by remaining matrix deposition, hyperproliferating epithelium and scar formation, persistent inflammatory infiltrates, increased susceptibility to subsequent infection, and impaired gas exchange function. Recent findings indicate that such responses might derive from an inflammation-driven or even pathogen-directed targeting of the stem cell niche; however, these processes have not been elucidated in detail to date.

Deciphering the key cellular and molecular events balancing effective host defense and beneficial epithelial stress responses versus parenchymal damage, overshooting inflammation and aberrant repair will provide novel targets of intervention to drive injury resolution and tissue repair while maintaining functional anti-bacterial and anti-viral host defense.

Long-term Scientific and Structural Objectives

The long-term aim of this research area is the identification of novel therapeutic strategies to resolve inflammation, promote injury resolution and enhance parenchymal repair in severe pneumonia/ARDS, while maintaining/fostering appropriate host defense and respecting the lung architectural requirements. To achieve this goal, we will substantially broaden our knowledge on the molecular and cellular events in place during different stages of pneumonia and post-pneumonia regeneration, as well as induction and resolution of non-microbial lung parenchymal attack. Transgenic mouse technology, humanized mouse models, small animal models, human lung organoid models and human biobank materials will be employed. Imaging and “omics” technologies will be scaled-down to the single cell level, but also applied to resolve intact organismal and systemic questions in animal models and human disease. Novel targets identified in these approaches and offering for therapeutic intervention will be addressed by employing screening platforms, small molecule libraries and innovative molecular tools. Moreover, cell-based therapies will further broaden the therapeutic armamentarium employed to restrain destructive tissue inflammation and induce lung parenchymal repair and regeneration. Such approaches will be forwarded to the clinical arena by capitalizing on the board expertise in investigator-initiated early trials and industry-sponsored clinical studies available in the scientific environment of the institute.