Abstract: Background: Localized lower respiratory tract infection including unilobar and round pneumonia can be associated with hypoxia and oxygen requirements. This is unexplained. Hypothesis: Spread of fluid absorption inhibiting cytokines in the alveolar spaces of the inflamed lung is cause of hypoxia in localized lower respiratory tract infection by spread of CFTR dysfunction in alveolar epithelial cells to more areas including those not infected. Evidence supporting the hypothesis: There is no evidence of pulmonary shunting to explain hypoxia in localized pneumonia. Systemic inflammatory response syndrome (SIRS) related generalized increase in alveolar capillary barrier or pulmonary vasoconstriction not visible on a chest x-ray cannot explain the hypoxia detected. Testing the hypothesis: Confirmation of the hypothesis could be achieved using pulmonary MRI or high resolution CT to confirm spread of alveolar fluid accumulation from the localized pneumonia focus as opposed to generalized SIRS related pulmonary oedema together with cytokine and chloride measurement in bronchoalveolar lavage samples from the lung segments near the affected lung segment and unaffected contralateral lung. Ventilation/perfusion scintigraphy could investigate for involvement of vasoconstriction or microemboli from intravascular coagulation. Implications of a confirmation of the hypothesis: Should the posed hypothesis be confirmed adjuvant strategies including small molecule CFTR activators and CFTR activating combination of beta-agonists, phosphodiesterase inhibitors and steroids could be used to treat hypoxia.