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Updated: Apr 16, 2026
Pseudofracture: An Acute Peripheral Tissue Trauma Model
Published on: April 18, 2011
Mitochondrial damage-associated molecular patterns from fractures suppress pulmonary immune responses via formyl
Haipeng Li1, Kiyoshi Itagaki, Nicola Sandler
1From the Department of Surgery (H.L., K.I., N.S., D.G., A.G., E.K., L.O., C.J.H.), Center for Vascular Biology Research (E.K.), and R&AA-Morphology Core (Y.Z.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Rutgers New Jersey Medical School (D.H.L.), Newark, New Jersey; Department of Orthopaedics (H.L.), Beijing Army General Hospital, Beijing, China; National Yang Ming University (Y.T.L., I.T.T.), Taipei, Taiwan; and Istanbul University Cerrahpasa Medical Faculty (B.I.), Istanbul, Turkey.
Background:
No known biologic mechanisms link tissue injury with pneumonia (PNA). Neutrophils (PMNs) are innate immune cells that clear bacteria from the lung by migration toward chemoattractants and killing bacteria in neutrophil extracellular traps (NETs). We predicted that tissue injury would suppress PMN antimicrobial function in the lung. We have also shown that mitochondria-derived damage-associated molecular pattern molecules from the bone can alter PMN phenotype and so hypothesized that formyl peptides (FPs) from fractures predispose to PNA by suppressing PMN activity in the lung.
Methods:
Animal studies involved the following. (1) Rats were divided into three groups (10 per condition) as follows: (a) saline injection in the thigh (b) Staphylococcus aureus (SA, 3 × 10) injected intratracheally, or (c) pseudofracture (PsFx; bone supernatant injected in the thigh) plus intratracheally injected SA. (2) Rats were divided into four groups as follows: (a) control, (b) pulmonary contusion (PC), (c) PsFx, and (d) PC + PsFx. Bronchoalveolar lavage was performed 16 hours later. Clinical studies involved the following. (3) Human bone supernatant was assayed for its FP-receptor (FPR) stimulation. (4) Trauma patients' PMN (n = 32; mean ± SE Injury Severity Score [ISS], 27 ± 10) were assayed for chemotaxis (CTX) or treated with Phorbol 12-myristate 13-acetate (PMA, Phorbol ester) and analyzed for NET formation.
Results:
In the animal studies, (1) SA was rapidly cleared by the uninjured mice and PsFx markedly suppressed lung bacterial clearance (p < 0.01). (2a) PC induces PMN traffic to the lung, but PsFx decreases PC-induced PMN traffic (p < 0.01). (2b) SA increased bronchoalveolar lavage PMN, and PsFx decreased that influx (p < 0.01). In the clinical studies, (3) bone supernatant activates PMN both via FPR-1 and FPR-2. (4) Trauma decreases PMN CTX to multiple chemokines. Circulating PMNs show NETs spontaneously after trauma, but maximal NET formation is markedly attenuated.
Conclusion:
Fractures may decrease lung bacterial clearance because FP suppresses PMN CTX to other chemoattractants via FPR-1/2. Trauma activates NETosis but suppresses maximal NETosis. Fractures decrease lung bacterial clearance by multiple mechanisms. PNA after fractures may reflect damage-associated molecular pattern-mediated suppression of PMN antimicrobial function in the lung.
Insights
Bone fractures impair lung bacterial clearance by suppressing neutrophil antimicrobial function. Formyl peptides from fractures reduce neutrophil migration and NET formation, increasing pneumonia risk after injury.
Area of Science:
- Immunology
- Pulmonology
- Trauma Research
Background:
- The biological link between tissue injury and pneumonia (PNA) is not well understood.
- Neutrophils (PMNs) are crucial for clearing lung bacteria via migration and neutrophil extracellular traps (NETs).
- Mitochondria-derived damage-associated molecular patterns from bone may alter PMN function.
Purpose of the Study:
- To investigate if tissue injury, specifically bone fractures, suppresses PMN antimicrobial function in the lung.
- To test the hypothesis that formyl peptides (FPs) from fractures predispose to PNA by suppressing PMN activity.
Main Methods:
- Animal studies: Rats exposed to Staphylococcus aureus (SA) with or without pseudofracture (PsFx) or pulmonary contusion (PC).
- Human studies: Assayed bone supernatant for FP-receptor (FPR) stimulation and analyzed trauma patients' PMNs for chemotaxis (CTX) and NET formation.
Main Results:
- Pseudofracture significantly suppressed lung bacterial clearance in rats challenged with SA.
- Bone supernatant activated human PMNs via FPR-1 and FPR-2.
- Trauma decreased PMN chemotaxis and attenuated maximal NET formation in patients.
Conclusions:
- Fractures may decrease lung bacterial clearance by suppressing PMN chemotaxis and NET formation.
- Formyl peptides released from fractures appear to mediate this suppression through FPR-1/2.
- PNA following fractures may result from damage-associated molecular pattern-mediated impairment of PMN function.
