By uncovering the mechanism by which fibrous tissue cells in the lung multiply, researchers at The Saban Research Institute of Children’s Hospital Los Angeles (CHLA), along with colleagues in Mexico and Canada, have identified a promising new approach for the treatment of pulmonary fibrosis.
Idiopathic pulmonary fibrosis or IPF- where the disease appears spontaneously and without a known cause - is a severe, chronic lung disease in which the rapid growth of fibrous tissue results in increasingly severe breathing difficulties and a high mortality rate.
Excessive signaling of the growth factor TGF-β is recognized as a central player in lung fibrosis, and its increased expression has been identified in both IPF patients and experimental models of the disease. However, in addition to its pro-fibrotic effect, TGF-β signaling is essential to aspects of other systems, such as appropriate immune response.
Therefore, complete therapeutic blockade of TGF-β pathway isn’t ideal, says the study’s principal investigator Wei Shi, MD, PhD, of the Developmental Biology and Regenerative Medicine research program at CHLA. “This is a very complicated signaling pathway, which promotes mesenchymal stem cell proliferation, while also acting as a tumor suppressant,” said Shi, who is also an associate professor in the Department of Surgery, Keck School of Medicine of the University of Southern California. “Our goal was to find a way to target specific cells that result in fibrosis without affecting other cells.”
Using a unique transgenic mouse model developed at The Saban Research Institute, the researchers were able to manipulate TGF-β signaling in adult lung mesenchymal cells at selected stages of lung fibrosis. They showed that the progression of fibrosis mediated by TGF-β was independent of early inflammatory processes during initiation of fibrosis - an understanding that is vital in designing therapeutic strategies to stop its progression in IPF patients.
Pulmonary fibrosis is a condition in which the tissue deep in your lungs becomes scarred over time. This tissue gets thick and stiff. That makes it hard for you to catch your breath, and your blood may not get enough oxygen.
Causes of pulmonary fibrosis include environmental pollutants, some medicines, some connective tissue diseases, and interstitial lung disease. Interstitial lung disease is the name for a large group of diseases that inflame or scar the lungs. In most cases, the cause cannot be found. This is called idiopathic pulmonary fibrosis.
Shortness of breath
A dry, hacking cough that doesn’t get better
Weight loss for no known reason
Aching muscles and joints
Clubbing, which is the widening and rounding of the tips of the fingers or toes
Your doctor may use your medical history, imaging tests, a biopsy, and lung function tests to diagnose pulmonary fibrosis. There is no cure. Treatments can help with symptoms and improve your quality of life. They include medicines, oxygen therapy, pulmonary rehabilitation, or a lung transplant.
Secondly, they identified a downstream gene called P4HA3 that is important to the overabundant collagen deposition associated with IPF. This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis. Inhibition of this enzyme was shown to reduce the TGF-β-stimulated collagen production in both cultured fibroblasts (connective tissue cells that produces collagen) and mouse models of lung fibrosis.
“Our data indicate that increased expression of collagen prolyl hydroxylase is one of the important mechanisms underlying the proliferation of fibrous tissue that is mediated by TGF-β. Inhibiting this enzyme appears to be a promising therapy to interfere with excessive collagen production and deposition in IPF patients,” Shi concluded.
How is pulmonary fibrosis diagnosed?
Pulmonary fibrosis is suggested by a history of progressive (worsening over time) shortness of breath with exertion. Sometimes, during examination of the lungs with a stethoscope, the doctor can hear crackling sounds in the chest. These crackles have a very characteristic sound and are very similar to the sound heard when Velcro is pulled apart. These are often referred to as “Velcro crackles (or rales)”. The chest X-ray may or may not be abnormal. However, a special X-ray test called a high resolution CT scan will frequently demonstrate abnormalities. This type of X-ray provides a cross-sectional picture of the lungs in very detailed resolution. The classic findings in idiopathic pulmonary fibrosis show diffuse peripheral scarring of the lungs with small bubbles (known as bullae) adjacent to the outer lining of the surface of the lung, often at the bases of the lungs.
Lung function testing is distinctly abnormal. The volumes of the lungs may be reduced, as may the airflow, but the characteristic finding is a reduction in the diffusing capacity. The diffusing capacity is a measure of the ability of the lungs to exchange gases (oxygen and carbon dioxide) into and out of the blood stream.
The diagnosis can be confirmed by lung biopsy. An open surgical biopsy, meaning that the chest wall must be surgically opened under general anesthesia to remove a portion of lung tissue, may be necessary to obtain enough tissue to make an accurate diagnosis. The most common type of biopsy in this situation is by a video assisted thoracoscope. Basically, this involves placing a small tube into the chest cavity through which biopsy samples can be obtained. Often, if the clinical situation is very classical in presentation, a biopsy may be unnecessary. The biopsy specimen is examined microscopically by a pathologist to confirm the presence of fibrosis.
Additional contributors to the study include first author Yongfeng Luo and Wei Xu, David Warburton, Hui Chen and Rachel Dong of Children’s Hospital Los Angeles and Keck School of Medicine of the University of Southern California; Bangping Qian of Nanjing Drum Tower Hospital, Nanjing, China; Moisés Selman, Instituto Nacional de Enfermedades Respiratorias, Mexico; and Jack Gauldie and Martin Kolb, McMaster University, Hamilton, Ontario, Canada.
This work was supported in part by NIH Grants HL109932 and HL068597, a California Institute of Regenerative Medicine Training Grant, and the Canadian Institute for Health Research.
About Children’s Hospital Los Angeles
Children’s Hospital Los Angeles has been named the best children’s hospital on the West Coast and among the top five in the nation for clinical excellence with its selection to the prestigious U.S. News & World Report Honor Roll. Children’s Hospital is home to The Saban Research Institute, one of the largest and most productive pediatric research facilities in the United States. Children’s Hospital is also one of America’s premier teaching hospitals through its affiliation since 1932 with the Keck School of Medicine of the University of Southern California.
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Journal of Pathology