Generally fibrosis is associated with activated fibroblast, also called as Myofibroblast. Activation of fibroblast to myofibroblast is promoted by inflammation. Inflammation acts as a source of cytokines (Pro-fibrogenic) like TGF-beta, CTGF etc. which acts on fibroblast to activate them (myofibroblasts) for producing different collagen isoforms, Interestingly it is observed that the source of these cytokines is epithelial cells which in response to the external stimuli (injury) secretes these cytokines. These cytokines intern acts on fibroblast cells to make them myofibroblast. As inflammation is also a good source of these profibrogenic cytokines, fibrosis becomes more severe in chronic cases.

@ Imran Khan;

Yes, you are right. But fibrocytes circulate from bone marrow into the lung tissue. They proliferate and differentiate to myofibroblasts. If you want to compare fibroblasts against fibrocytes, what will you find? Which one is more important?

Then you mean that fibrosis is followed by inflammation. This is true but we should consider that in asthma, fibrosis is dominated but in COPD inflammation is dominated. If you were to decide on a specific cell what would you do? (inflammation and fibrosis separatedly). Thanks

@ sadegh jamalkandi

Well tissue injury leading to either inflammation or fibrosis in different conditions is not known. But as far as your question is concerned a combined staning of A-SMA and CD34+, CD45+ could tell you that in lung fibrosis or lung inflammation (COPD); out of all activated fibroblast what percentage is contributed by the fibrocytes.

Dear Michael;

I wonder if you know a good reference about cell-cell interaction in lung. Your answer was really interesting for me. It was exactly what I was sensing. I think that epithelial cells are commander but I have no clue for this. It seems logically that a resident cell should quid other cells. Accordingly, after injury, epithelial cells secrete 3 kind of proteins: 1) TGF-b for cell proliferation and differentiation, 2) inflammatory cytokines and 3) recruitment of fibrocytes from bone marrow. Then who should be leader. epithelium seem logical.

@ Michael Roth

Thanks, I have studied the introduced papers.

Lets imagine the epithelium injury. Injured epithelium cells will secrete inflmmatory, fibrotic cytokines and chemokines. These cells are dictating that there is an injury. Tissue repair system should amplify the multipotent cells and differentiate them to epithelial cells. Cell migeration also needs ECM degradation and temporary ECM construction in which fibroblasts and fibrocytes can migrate. Here, epithelial cells are leader, aren't they?

Then, epithelial cells should change the signaling toward resolution of the wound. This means:

Inhibition of inflammatory signaling --------and induction of anti-inflammatory signaling. simultaneously those multipotent cells and recruited immune cells should leave the area or should die via apoptosis.

This seems logically that, epithelial layer should produce signals for start and endpoint of injury through Treg cells.

What is your idea?

Hi Sadegh, if I may butt in here as well...

I also don't think, that there is a leader-slave scenario going on, but if you look at it from a chronological point of view, there has to be (at least in the beginning after the initial insult) a sequence of events.

Here's my simplified and admittedly immune system centered view:

Injured cells will (passively when undergoing necrosis) release plenty of so called alarmins (DNA, actin, HMGB1, IL33....). These activate resident and recruit circulating immune cells, which then take over the orchestration of the following events. The very first 'set' of infiltrating immune cells (neutrophils...), release factors that recruit the next range, and so on. Immune cells are also crucial in initiating healing and regeneration responses, they produce new extracellular matrix and activate structural cells to proliferate.

Mast cells and Natural Helper Cells are known to be very important in lung inflammation and tissue homeostasis. There are a view really nice reviews out there...

So, I wouldn't call epithelial cells 'leader'. They are the cell type first affected by injury, but they have a rather passive role. Surrounding immune cells actively react to what's going on. Injured epithelial cells are cleaned away and that's it then for them... It's also the immune cells that initiate resolution and regeneration.

Why then, there is chronic inflammation, fibrosis and scars... if we just knew, so many are trying to find out.