MCP-1 Antibody Treatment Enhances Damage and Impedes Repair of the Alveolar Epithelium in Influenza Pneumonitis

Abstract

Recent studies have demonstrated an essential role of alveolar macrophages during influenza virus infection. Enhanced mortalities were observed in macrophage-depleted mice and pigs after influenza virus infection, but the basis for the enhanced pathogenesis is unclear. This study revealed that blocking macrophage recruitment into the lungs in a mouse model of influenza pneumonitis resulted in enhanced alveolar epithelial damage and apoptosis, as evaluated by histopathology, immunohistochemistry, Western blot, RT-PCR, and TUNEL assays. Abrogation of macrophage recruitment was achieved by treatment with monoclonal antibody against monocyte chemoattractant protein-1 (MCP-1) after sub-lethal challenge with mouse-adapted human influenza A/Aichi/2/68 virus. Interestingly, elevated levels of hepatocyte growth factor (HGF), a mitogen for alveolar epithelium, were detected in bronchoalveolar lavage samples and in lung homogenates of control untreated and nonimmune immunoglobulin (Ig)G-treated mice after infection compared with anti-MCP-1-treated infected mice. The lungs of control animals also displayed strongly positive HGF staining in alveolar macrophages as well as alveolar epithelial cell hyperplasia. Co-culture of influenza virus-infected alveolar epithelial cells with freshly isolated alveolar macrophages induced HGF production and phagocytic activity of macrophages. Recombinant HGF added to mouse lung explants after influenza virus infection resulted in enhanced BrdU labeling of alveolar type II epithelial cells, indicating their proliferation, in contrast with anti-HGF treatment showing significantly reduced epithelial regeneration. Our data indicate that inhibition of macrophage recruitment augmented alveolar epithelial damage and apoptosis during influenza pneumonitis, and that HGF produced by macrophages in response to influenza participates in the resolution of alveolar epithelium.

Influenza virus-induced lung injury: pathogenesis and implications for treatment

“…Monocyte-derived alveolar macrophages were found to secrete hepatocyte growth factor (HGF), a potent lung epithelial cell mitogen, which induced proliferation of type II alveolar epithelial cells in a mouse IAV infection model [154,155]. Tissue resident alveolar macrophages promote the regeneration of type II alveolar epithelial cells after endotoxin-induced lung injury via a pathway that requires TNF-α and GM-CSF, another proliferative and anti-apoptotic factor for the lung epithelium [156,157].…”

“…Whether this is accompanied by expansion of other progenitor pools or whether direct or immune-mediated damage to the more distal progenitor populations in response to viral infection necessitates the expansion of the airway stem cell pool is not known. Soluble growth factors involved in these responses comprise, among others, fibroblast growth factors, EGFs, HGFs, and transforming growth factor-β [158], some of which are induced in IAV infection [150,154,162,163]. Our own data reveal that a itgb4 + progenitor cell population is crucial for bronchial and alveolar repair after IAV-induced lung injury in mice, a process involving cross-talk with resident mesenchymal niche cells, extracellular matrix laminins and FGF10 (S. Herold and G.R.S.…”

Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms

“…McKinstry et al, unpublished observations). It is possible that factors released by macrophages activated by memory CD4 + T cells (11,46) may stimulate epithelial proliferation, setting up conditions that allow for chronic infection, increasing lung inflammation, and eventually, death of SCID mice regardless of the emergence of escape mutants.…”

Relationship among MIF, MCP-1, viral loads, and HBs Ag levelsin chronic hepatitis B patients

“…In one study, peripheral CD4+ T-cell and cytotoxic T-lymphocyte responses to chronic infection were weak and narrowly focused (25) In studies conducted with parvovirus B19-dengue virus (28) and HIV-infected patients (29,30), MCP-1 levels were positively correlated with the viral loads. In studies of the influenza virus, anti-MCP-1 treatment significantly reduced the infiltration of macrophages into the lungs, and blocking MCP-1 reduced the neutrophil population in bronchoalveolar lavage (31). Increased viral loads were observed in MCP-1 knockout mice, with reduced leukocyte recruitment to the infected lungs (32).…”