Fibrotic development in the lungs may result from an inflammatory independent pathway involving the cytokines (signaling proteins necessary for immune response) TGF-β and IL-1β, explained Jack Gauldie, chair of Pathology and Molecular Medicine at McMaster University, in a lecture on Idiopathic Pulmonary Fibrosis (IPF) this past Wednesday. IPF is a highly lethal disorder with a 50 percent mortality rate over a three-year period. Symptoms and eventual death result from the deposition of excess fibrotic tissue in the extracellular space of the lung.
According to Gauldie, the traditional bodily reaction to injury of organ tissue is an inflammatory response, essential for triggering scar tissue induction and the subsequent replacement of scar tissue with normal epithelium. This process constantly occurs within the lungs due to the steady influx of irritants and foreign pathogens. In his lecture, Gauldie explored how this normal acute immune response develops into chronic fibrosis.
It is clear that fibrosis does not simply result from repeated inflammation, since anti-inflammatory drugs do not stem the progression of the disease. Thus, researchers thought it was possible the disease results from an altogether separate pathway. Gauldie’s lab attempted to explore this process by over-expressing certain cytokines via a virus vector in neonatal rodents. Two factors, IL-1β and TGF-β, appeared to trigger a fibrotic response.
Over-expression of TGF-β only lasts for approximately seven to 10 days before endogenous mechanisms bring cytokine levels back to baseline. However, this relatively transient upsurge of expression resulted in IPF pathology (dense extracellular matrix, honeycomb patterns, excess fibroblastic structures) almost 60 days later, emphasizing the importance of the TGF-β pathway in fibrotic development. IL-1β produced similar fibrotic pathology except it also induced inflammation. Further examination of the IL-1β, however, indicated that fibrosis occurred because IL-1β activated the TGF-β pathway.
SMAD-3 knockouts and treatment of rodents with TNFα further confirmed Gauldie’s theories. SMAD-3 is an essential gene for TGF-β and knockouts showed considerable resistance to IPF progression. Conversely, TNFα is an inflammatory agent; however, it did not produce a fibrotic response since it does not act through the TGF-β pathway. This result further confirmed the inflammation independent nature of fibrosis.
The tissue specific, yet diffusive nature of fibrosis was another mystery which Gauldie’s group attempted to unravel. Fibrosis is not exclusive to the lungs and can develop in many other organ systems; however, fibrosis never spreads between different organs and rather, progresses in a very tissue-specific manner. Thus, the agent responsible for fibrosis is probably not a soluble or readily diffusible product. The culprit most likely lies within the dense extracellular matrix surrounding and connecting the pulmonary cells.
The extracellular matrix can “capture” growth factors such as TGF-β and spread these factors to further cells, creating a “pro-fibrotic microenvironment,” Gauldie said. Growth factors, and hence fibrosis, spread throughout contiguous tissue via this matrix, while remaining restricted to a particular tissue type. Another key to this signaling mechanism are integrins, cell surface receptors that can interact with the extracellular matrix. Integrins in unaffected cells received the TGF-β signal from the microenvironment, resulting in further spread of the fibrosis.
Therapy targeting the TGF-β pathway and the extracellular matrix may be effective in slowing or even halting the progression of IPF.
Listen to a DUJS Podcast of Jack Gauldie’s lecture: