Depletion of Bone Marrow CCSP-Expressing Cells Delays Airway Regeneration

Abstract

The contribution of bone marrow cells (BMC) in lung repair is controversial. We previously reported a subpopulation of BMC that express Clara cell secretory protein (CCSP). To determine the contribution of endogenous CCSP(+) BMC to airway regeneration, we performed bone marrow transplantation studies using the CCtk mouse, which expresses a thymidine kinase suicide gene under regulation of the CCSP promoter. Mice were transplanted with wild-type or CCtk BMC and treated with ganciclovir to eliminate CCSP(+) cells. After airway injury using naphthalene, mice depleted of CCSP(+) BMC had more inflammatory cells in lung and decreased levels of oxygen in arterial blood. They also had reduced expression of airway epithelial genes and less Clara cells compared to control mice that had intact CCSP(+) BMC and bone marrow derived CCSP(+) cells in the airways. After naphthalene injury, administration of CCSP reproduced the beneficial effect of CCSP(+) BMC by improving recovery of airway epithelium, reducing lung inflammation and increasing oxygen in arterial blood from mice depleted of CCSP(+) BMC. Our data demonstrate that ablation of CCSP(+) BMC delays airway recovery and suggests the beneficial effect of CCSP(+) BMC in lung recovery is in part due to production of CCSP itself.

Club cells and CC16: another “smoking gun”? (With potential bullets against COPD)

“…The identification of a receptor for CC16 would represent the next step to better understand this hypothesis. Since CYP2F2 disappeared with CC16 knockout in the present study, this raised the question of whether interfering with the protein also interfered with the cell, and subsequently, the question of whether protein or cell was the most important player in the field [16].…”

“…Recently, CC16-expressing cells from the bone marrow were shown to participate in airway epithelial regeneration [16]. With regard to the human therapeutic perspective, it is of great importance to identify the optimal timing of initiation and especially whether it should occur before or after smoking cessation.…”

Club Cell Protein 16 (CC16) Augmentation: A Potential Disease-modifying Approach for Chronic Obstructive Pulmonary Disease (COPD)

“…These cells also express CD45 (the common leukocyte antigen), and mesenchymal markers (e.g., CD73, CD90, and CD105), and are involved in alveologenesis and lung epithelial renewal. A recent study showed that CC16 + BMC regulate epithelial repair and lung inflammatory responses to injury 20 . In the latter study, CC16 + BMC were depleted in mice by transplanting their bone marrow with bone marrow from transgenic mice expressing a thymidine kinase suicide gene under the control of the CC16 promoter.…”

“…When mice were treated with ganciclovir, this treatment selectively depleted all CC16-expressing BMC cells expressing thymidine kinase by generating an intracellular toxic metabolite of thymidine kinase. When challenged with naphthalene to induce acute lung injury, recipients that had CC16 + BMC depleted with ganciclovir had a slower rate of recovery of airway epithelial cell proliferation, higher leukocyte counts in bronchoalveolar lavage (BAL) samples, and lower arterial blood oxygen saturation levels than mice receiving WT BMC 20 . Interestingly, delivering recombinant murine CC16 by the intra-tracheal route to recipients lacking CC16 + BMC reduced these naphthalene-induced changes 20 .…”

“…Thus, rCC16 therapy might be feasible as a therapeutic approach for COPD patients having low CC16 blood and lung levels. Thus far, rCC16 therapy has only been tested in naphthylene-treated mice lacking CC16+ BMCs 20 . Delivering 30 μg of rmCC16 to these mice daily by the intra-tracheal route beginning 24 h after naphthalene delivery reduced lung leukocyte counts, improved blood oxygen saturation levels, and surprisingly increased airway CC16 expression in the animals, suggesting that rCC16 limits Club cell injury and stabilizes endogenous production of CC16 by airway cells.…”