The transition from normal lung anatomy to minimal and established fibrosis in idiopathic pulmonary fibrosis (IPF)
Feng Xu,
Naoya Tanabe,
Dragos M. Vasilescu,
John E. McDonough,
Harvey O. Coxson,
Kohei Ikezoe,
Daisuke Kinose,
Kevin W. Ng,
Stijn E. Verleden,
Wim A. Wuyts,
Bart M. Vanaudenaerde,
Johny Verschakelen,
Joel D. Cooper,
Marc E. Lenburg,
Katrina B. Morshead,
Alexander R. Abbas,
Joseph R. Arron,
Avrum Spira,
Tillie-Louise Hackett,
Thomas V. Colby,
Christopher J. Ryerson,
Raymond T. Ng,
James C. Hogg
Affiliations
Feng Xu
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada
Naoya Tanabe
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Dragos M. Vasilescu
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada
John E. McDonough
Leuven Lung Transplant Unit, KU Leuven and UZ Gasthuisberg, Leuven, Belgium
Harvey O. Coxson
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada
Kohei Ikezoe
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada
Daisuke Kinose
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada; Division of Respiratory Medicine, Department of Medicine, Shiga University of Medical Science, Shiga, Japan
Kevin W. Ng
The Francis Crick Institute, London, UK
Stijn E. Verleden
Laboratory of Respiratory Diseases, BREATHE, Department of CHROMETA, KU Leuven, Leuven, Belgium
Wim A. Wuyts
Leuven Lung Transplant Unit, KU Leuven and UZ Gasthuisberg, Leuven, Belgium
Bart M. Vanaudenaerde
Leuven Lung Transplant Unit, KU Leuven and UZ Gasthuisberg, Leuven, Belgium
Johny Verschakelen
Leuven Lung Transplant Unit, KU Leuven and UZ Gasthuisberg, Leuven, Belgium
Joel D. Cooper
Division of Thoracic Surgery, University of Pennsylvania, USA
Marc E. Lenburg
Boston University Medical Center, Boston, MA, USA
Katrina B. Morshead
Genentech, Inc., South San Francisco, CA, USA
Alexander R. Abbas
Genentech, Inc., South San Francisco, CA, USA
Joseph R. Arron
Genentech, Inc., South San Francisco, CA, USA
Avrum Spira
Boston University Medical Center, Boston, MA, USA
Tillie-Louise Hackett
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada
Thomas V. Colby
Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, USA
Christopher J. Ryerson
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada; Department of Medicine, The University of British Columbia, Vancouver, Canada
Raymond T. Ng
Department of Computer Science, The University of British Columbia, Vancouver, Canada
James C. Hogg
Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada; Corresponding author.
Background: The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition. Methods: Pre-operative thoracic Multidetector Computed Tomography (MDCT) scans of patients with severe IPF (n = 9) were used to identify regions of minimal(n = 27) and established fibrosis(n = 27). MDCT, Micro-CT, quantitative histology, and next-generation sequencing were used to compare 24 samples from donor controls (n = 4) to minimal and established fibrosis samples. Findings: The present results extended earlier reports about the transition from normal lung anatomy to minimal and established fibrosis by showing that there are activations of TGFBI, T cell co-stimulatory genes, and the down-regulation of inhibitory immune-checkpoint genes compared to controls. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming lymphoid follicles. Moreover, fibrosis pathways, mucin secretion, surfactant, TLRs, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis. Interpretation: The transition from normal lung anatomy to minimal and established fibrosis is associated with genes that are involved in the tissue repair processes, the activation of immune responses as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events correlate with the development of structural abnormality of IPF and probably contribute to its pathogenesis.
