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Bone marrow transplantation reveals an essential synergy between neuronal and hemopoietic cell neurokinin production in pulmonary inflammation
Mara Chavolla-Calderón, … , Meggan K. Bayer, J. Julio Pérez Fontán
Mara Chavolla-Calderón, … , Meggan K. Bayer, J. Julio Pérez Fontán
Published April 1, 2003
Citation Information: J Clin Invest. 2003;111(7):973-980. https://doi.org/10.1172/JCI17458.
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Article Pulmonology

Bone marrow transplantation reveals an essential synergy between neuronal and hemopoietic cell neurokinin production in pulmonary inflammation

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Abstract

Neurogenic inflammation is believed to originate with the antidromic release of substance P, and of other neurokinins encoded by the preprotachykinin A (PPT-A) gene, from unmyelinated nerve fibers (C-fibers) following noxious stimuli. Consistent with this concept, we show here that selective sensory-fiber denervation with capsaicin and targeted deletion of the PPT-A gene protect murine lungs against both immune complex–mediated and stretch-mediated injuries. Reconstitution of PPT-A gene–deleted mice with WT bone marrow does not abrogate this protection, demonstrating a critical role for PPT-A gene expression by sensory neurons in pulmonary inflammation. Surprisingly, reconstitution of WT mice with PPT-A gene–deficient bone marrow also confers protection against pulmonary injury, revealing that PPT-A gene expression in hemopoietic cells has a previously unanticipated essential role in tissue injury. Taken together, these findings demonstrate a critical synergy between capsaicin-sensitive sensory fibers and hemopoietic cells in neurokinin-mediated inflammation and suggest that such synergy may be the basis for a stereotypical mechanism of response to injury in the respiratory tract.

Authors

Mara Chavolla-Calderón, Meggan K. Bayer, J. Julio Pérez Fontán

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Figure 1

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Attenuation of immune complex–mediated injury by PPT-A gene deletion and...
Attenuation of immune complex–mediated injury by PPT-A gene deletion and capsaicin-selective sensory denervation. (a) Bronchoalveolar lavage fluid obtained after intravenous injection of chicken ovalbumin and intratracheal instillation of a polyclonal antibody against ovalbumin shows alveolar hemorrhage in WT mice, but not in mice with targeted deletion of the PPT-A gene (PPT-A–/–). (b) Casein zymogram demonstrates increased bronchoalveolar lavage fluid protease activity in WT compared with PPT-A–/– and capsaicin-denervated mice. The proteolytic bands visible in the illustration have the electrophoretic mobility profiles of matrilysin and macrophage metalloelastase. Black arrowheads indicate molecular weight markers. (c) Erythrocyte and neutrophil counts in the bronchoalveolar lavage fluid, Evans blue lavage/serum concentration ratios, and TNF-α levels in the bronchoalveolar lavage fluid demonstrate protection against immune complex injury by PPT-A gene deletion and capsaicin denervation (P < 0.0001, except for TNF-α levels where P = 0.01). Cell counts and Evans blue ratios (black bars; n = 18 WT, 11 PPT-A–/–, and 19 capsaicin) are compared with those of control mice injected intravenously with ovalbumin and intratracheally with normal saline (white bars; n = 8 WT, 2 PPT-A–/–, and 12 capsaicin). TNF-α levels were measured in fewer mice (n = 10 WT, 7 PPT-A–/–, and 11 capsaicin). Values are shown as mean ± SE, except for TNF-α levels, which are shown as median and 25th to 75th percentile span.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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