{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:30:15Z","timestamp":1790857815314,"version":"4.1.0"},"reference-count":49,"publisher":"American Society for Clinical Investigation","issue":"17","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,20]]},"abstract":"<jats:p>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-\u03b2 production by HPS macrophages, which was eliminated by CCR2 deletion. Selective deletion of TGF-\u03b2 in myeloid cells or of TGF-\u03b2 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-\u03b2, thus amplifying the fibrotic cascade through AEC apoptosis and stimulation of fibrotic remodeling.<\/jats:p>","DOI":"10.1172\/jci.insight.88947","type":"journal-article","created":{"date-parts":[[2016,10,19]],"date-time":"2016-10-19T11:00:59Z","timestamp":1476874859000},"source":"Crossref","is-referenced-by-count":98,"title":["Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome"],"prefix":"10.1172","volume":"1","author":[{"given":"Lisa R.","family":"Young","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Pulmonary Medicine, and"},{"name":"Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA."},{"name":"Department of Cell 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