Dr. McCormack began his talk by giving a short review of lung anatomy. He described the bronchial system as an upside-down tree with the trachea equal to the trunk of the tree. The trachea branches into the main left and right bronchial tubes, and the alveolar sacs correspond to leaves on a tree. The exchange of gases occurs in these alveolar sacs. The delicate walls of the alveolar sacs are filled with capillaries. The blood needs to get as close as possible to the air spaces so that the gases can be exchanged. Normally, oxygen diffuses across the thin alveolar wall into the red blood cells and carbon dioxide transfers from the red blood cells into the sacs. But when a woman has LAM, LAM cells infiltrate the alveolar wall, thickening it, and thereby increasing the distance between the oxygen and the blood. These thicker alveolar walls limit the diffusion of oxygen. Somehow the proliferation and infiltration of LAM cells break down lung tissues, causing the cystic changes in the lungs. The cystic spaces then coalesce and remodel the lung.

Three research developments in LAM have uncovered these clues.

We now know that LAM not only occurs in women with Tuberous Sclerosis (TSC), it is common. There is strong evidence that LAM and TSC have an association. Studies are showing that 26-40% of women with TSC also have LAM. (Jay Ryu, Mayo Clinic; Joel Moss, NIH; David Franz, Cincinnati).

We also know that TSC mutations are found in the lungs of LAM patients who do not have TSC. (Lisa Henske, Fox Chase Cancer Centre).

Finally, LAM cells make enzymes (metallo-proteinases) that break down lung tissue.(NHLBI and AFIP, Matsui, Hayashi, Moss, Travis, and Ferrans). So, scientists are now more confident the relationship between LAM and TSC is a casual one or a causal one. TSC is caused by genetic mutations in either of two genes: TSC1 and TSC2. The TSC1 gene encodes the protein hamartin, the TSC2 gene, tuberin. Both hamartin and tuberin regulate cell growth. LAM has been described in TSC patients with either TSC1 or TSC2 mutations, which in those patients are almost always found in every cell in the body. In contrast, in sporadic LAM patients TSC2 mutations have only been found in the lung and the kidney. This is an unusual situation but it has been described in other diseases.

Dr. McCormack explained that cells usually regulate their growth in response to external proteins and hormones. Signals from the outside of the cell are transmitted to the nucleus along signalling pathways that can be thought of as a telegraph system. Genes then make proteins that tell the cells to grow or to stop growing, to divide or to stop dividing, to move or to stop moving, and to alter other cell functions. One hypothesis is that tuberin may play a role in signalling pathways that control cell growth in LAM. The absence of tuberin may take the brakes off and allow the cell to continue growing.

Estrogen regulates gene expression and growth in smooth muscle cells. Dan Noonan has uncovered a possible link between estrogen pathways that contro gene expression and the tuberin pathway. His hypothesis is that tuberin reacts with the estrogen/estrogen receptor complex and blocks the transmission of the estrogen signal to the cell nucleus. The result: no growth genes are turned on. In the absence of tuberin, estrogen growth signals are transmitted to the nucleus; the cell grows inappropriately. Cells regulate their growth in response to contact with other cells. If cells get too crowded, they may stop growing. Another hypothesis for LAM is that without hamartin, cells may not sense the overcrowding and, therefore, may keep growing.

Another possible mechanism for accumulation of LAM cells in the lung is the failure of cells to die. LAM cells may live too long. They may accumulate because they fail to die normally by a process called "apoptosis".

In summary, LAM cells may accumulate in the lung for a number of reasons. They may receive inappropriate external stimuli to grow; they may have defects in pathways that control cell growth; they may have defects in pathways that control cell death; or they may have defects in pathways that sense overcrowding or other aspects of their surroundings.