transforming-growth-factor-beta and Hermanski-Pudlak-Syndrome

Idiopathic pulmonary fibrosis (IPF) is an under-recognised, rare, progressive disease of the lungs with unknown aetiology and high mortality. The currently advocated pathogenic mechanism is represented by progressive multifocal fibrosis. It is diagnosed based on clinical, radiographic, physiological and histopathological criteria. Existing therapeutic guidelines recommend anti-inflammatory and immunosuppressive combinations, despite proven limited efficacy. There is no therapy approved specifically for IPF, but several antifibrotic agents are currently under development for this indication. Pirfenidone is an antifibrotic agent potentially effective for IPF therapy, and preclinical and available clinical data support its use in IPF. Future clinical studies are expected to provide more consistent information on survival benefit, lung function and health-related quality of life.

Topics: Administration, Oral; Amiodarone; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bleomycin; Cell Line; Clinical Trials, Phase II as Topic; Connective Tissue Growth Factor; Cricetinae; Cyclophosphamide; Drug Evaluation, Preclinical; Drugs, Investigational; Fibroblasts; Hermanski-Pudlak Syndrome; Humans; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Lung Transplantation; Mice; Orphan Drug Production; Photosensitivity Disorders; Pulmonary Fibrosis; Pyridones; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Transforming Growth Factor beta; Treatment Outcome; Tumor Necrosis Factor-alpha

Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic remodeling are incompletely understood. Since increased macrophage recruitment precedes pulmonary fibrosis in HPS, we investigated whether crosstalk between AECs and macrophages determines fibrotic susceptibility. We found that AECs from HPS mice produce excessive MCP-1, which was associated with increased macrophages in the lungs of unchallenged HPS mice. Blocking MCP-1/CCR2 signaling in HPS mice with genetic deficiency of CCR2 or targeted deletion of MCP-1 in AECs normalized macrophage recruitment, decreased AEC apoptosis, and reduced lung fibrosis in these mice following treatment with low-dose bleomycin. We observed increased TGF-β production by HPS macrophages, which was eliminated by CCR2 deletion. Selective deletion of TGF-β in myeloid cells or of TGF-β signaling in AECs through deletion of TGFBR2 protected HPS mice from AEC apoptosis and bleomycin-induced fibrosis. Together, these data reveal a feedback loop in which increased MCP-1 production by dysfunctional AECs results in recruitment and activation of lung macrophages that produce TGF-β, thus amplifying the fibrotic cascade through AEC apoptosis and stimulation of fibrotic remodeling.

Topics: Animals; Bleomycin; Chemokine CCL2; Disease Susceptibility; Epithelial Cells; Female; Hermanski-Pudlak Syndrome; Macrophages; Male; Mice; Mice, Inbred C57BL; Protein Serine-Threonine Kinases; Pulmonary Alveoli; Pulmonary Fibrosis; Receptor, Transforming Growth Factor-beta Type II; Receptors, CCR2; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta