GHRP-2 pretreatment attenuates LPS-induced acute lung injury in rats via NF-κB suppression
Background
Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are the leading complications of sepsis, carrying persistently high mortality in critically ill patients. No targeted pharmacological therapy reliably limits the fulminant pulmonary inflammation that drives ALI progression. Ghrelin's endogenous receptor GHSR has emerged as a tractable anti-inflammatory target, with ghrelin itself showing benefit in inflammatory disease models. GHRP-2 is a synthetic ghrelin agonist already studied in growth-hormone contexts, but its capacity to restrain the NF-κB-driven cytokine cascade in lung tissue had not been evaluated prior to this work.
Study Design
Male Sprague-Dawley rats received intratracheal instillation of LPS (2 mg/kg) to induce ALI. The treatment group received a subcutaneous injection of GHRP-2 (100 µg/kg) 0.5 h before LPS challenge; controls received vehicle. Lungs were harvested at 6 h post-LPS. Primary endpoints included histopathological examination of lung tissue, wet-to-dry weight ratio for edema, myeloperoxidase (MPO) activity for neutrophil infiltration, bronchoalveolar lavage fluid (BALF) total cell count and protein for permeability, ELISA-based TNF-α and IL-6 quantification, and NF-κB activity assay in lung homogenates.
Results
LPS instillation produced marked histopathological lung tissue injury confirmed at 6 h, alongside significantly elevated wet-to-dry weight ratios indicating pulmonary edema. MPO activity in lung tissue was substantially increased, reflecting heavy neutrophil infiltration. BALF analysis demonstrated significant rises in total cell count and total protein concentration, consistent with disrupted alveolar–capillary barrier integrity. Proinflammatory cytokines TNF-α and IL-6 were markedly elevated in BALF after LPS challenge.
Pretreatment with GHRP-2 (100 µg/kg s.c.) markedly suppressed
NF-κBactivation in lung tissues and attenuated all measured lung injury indices — edema, MPO activity, BALF permeability markers, TNF-α, and IL-6 — compared with LPS-only controls.
The authors conclude that inhibition of the NF-κB pathway represents at least a partial mechanistic explanation for GHRP-2's protective effect, positioning the peptide as a potential early-intervention therapeutic for ALI.
Key Findings
- GHRP-2 100 µg/kg s.c. given 30 min pre-LPS attenuated all measured ALI indices at 6 h
- Lung edema (wet-to-dry ratio) and MPO-measured neutrophil infiltration were reduced by GHRP-2 pretreatment
- BALF total cell count and protein concentration were significantly lowered versus LPS-only controls
- TNF-α and IL-6 levels in BALF were markedly reduced after GHRP-2 pretreatment
- NF-κB activation in lung tissue was markedly suppressed by GHRP-2, indicating a mechanistic pathway
Why It Matters
GHRP-2's protective window — a single subcutaneous dose 30 minutes before injury — highlights a prophylactic or peri-operative protocol angle relevant to high-risk surgical or septic patients who can be identified in advance. For clinicians and researchers monitoring the ghrelin-axis literature, this study extends GHRP-2's known anti-inflammatory portfolio beyond gut and cardiac models into the pulmonary compartment. The NF-κB mechanism is actionable: it aligns GHRP-2 with other NF-κB-targeting strategies and raises combinatorial questions with glucocorticoids or IL-6 antagonists. Translation remains early-stage — dose-ranging, therapeutic (post-injury) timing, and toxicity profiling in larger mammals are all absent, so no clinical protocol can yet be derived from this data alone.
