Ischemia-Reperfusion Injury Mechanisms in Pulmonary and Intestinal Systems

Ischaemia–reperfusion (I/R) injury arises when the restoration of blood flow to previously ischaemic tissue precipitates further cellular and microvascular damage. In the intestinal system, transient arterial occlusion compromises the mucosal barrier, leading to increased permeability, oxidative stress and activation of innate immune pathways. Reperfusion restores oxygen but generates reactive oxygen species (ROS), triggers endoplasmic reticulum (ER) stress and promotes inflammasome assembly, resulting in epithelial apoptosis, pyroptosis and systemic inflammatory responses. In the pulmonary system, I/R may occur during lung transplantation, acute embolic events or secondary to distant I/R insults, disrupting alveolar–capillary integrity, enhancing neutrophil infiltration and driving cytokine release. Cross-organ communication amplifies injury, as intestinal I/R can precipitate acute lung injury through translocated microbial products, systemic cytokines and leukocyte priming. Therapeutic strategies therefore aim to mitigate ROS generation, stabilise epithelial and endothelial barriers, regulate inflammasome activation and attenuate pro-inflammatory signalling, with broad implications for transplantation, critical care and surgical practice.

Research from Nature Portfolio

Investigations have identified inactive rhomboid protein 2 (iRhom2) as a crucial mediator of acute lung injury following intestinal I/R. Genetic deletion of iRhom2 attenuates the activation of tumour-necrosis factor-α converting enzyme, reduces caspase-3-dependent apoptosis in pulmonary tissue and dampens systemic TNF-α levels, thereby protecting alveolar integrity. Foundational studies on sterile inflammation have further elucidated the role of NLRP3 inflammasomes in I/R contexts, demonstrating that inflammasome assembly drives early cytokine maturation, cellular apoptosis and tissue injury, offering mechanistic parallels across organ systems and pointing towards inflammasome inhibition as a unifying therapeutic avenue.

Ischemia-Reperfusion Injury Mechanisms in Pulmonary and Intestinal Systems publication trend

The graph below shows the total number of articles in ischemia-reperfusion injury mechanisms in pulmonary and intestinal systems across all publications each year (not limited to Nature Index journals).

Technical terms

Ischaemia–reperfusion injury: Tissue damage elicited by restoration of blood flow and oxygen after a period of ischaemia, leading to oxidative stress and inflammation.

Inflammasome: A multiprotein cytosolic complex that senses cellular stress and activates inflammatory caspases to process interleukin-1β and interleukin-18.

Pyroptosis: Pro-inflammatory programmed cell death characterised by cell lysis and release of inflammatory mediators.

Endoplasmic reticulum stress: A state triggered by accumulation of misfolded proteins that activates adaptive or apoptotic cellular pathways.

Preconditioning: A protective strategy in which exposure to a mild stressor reduces damage from a subsequent severe insult.

References

1. Methane-Rich Saline Suppresses ER-Mitochondria Contact and Activation of the NLRP3 Inflammasome by Regulating the PERK Signaling Pathway to Ameliorate Intestinal Ischemia‒Reperfusion Injury. Inflammation (2023).
2. Sevoflurane ameliorates intestinal ischemia-reperfusion-induced lung injury by inhibiting the synergistic action between mast cell activation and oxidative stress. Molecular Medicine Reports (2015).
3. Role of iRhom2 in intestinal ischemia-reperfusion-mediated acute lung injury. Scientific Reports (2018).
4. Dexmedetomidine Ameliorates Lung Injury Induced by Intestinal Ischemia/Reperfusion by Upregulating Cannabinoid Receptor 2, Followed by the Activation of the Phosphatidylinositol 3‐Kinase/Akt Pathway. Oxidative Medicine and Cellular Longevity (2020).